潜能未定的克隆性造血（chip）

No abstract available

Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age‐related expansion of blood cells carrying preleukemic mutations, is associated with immune aging. This study aimed to investigate the association between CHIP and established autoimmune diseases.

Clonal hematopoiesis of indeterminate potential (CHIP) was associated with diabetes and cardiovascular diseases (CVD). However, the effect of CHIP on CVD have not been evaluated among patients with diabetes, and whether maintaining the healthy indictors could mitigate the adverse influence was also unclear. A total of 22,239 adults from the UK Biobank with diabetes and available whole-exome sequence data, and free of CVD were included. Multivariable-adjusted Cox regressions were used to explore the associations of any CHIP (variant allele fraction ≥ 2%), large CHIP (variant allele fraction ≥ 10%), and the top 10 commonly mutated driver genes for CHIP and with risk of CVD. The joint associations between health indicators (body mass index [BMI], HbA1c, blood pressure [BP], and low-density lipoprotein cholesterol [LDL]) and CHIP were further investigated. Over a median follow-up of 13.2 years, 5366 participants with diabetes developed CVD events. The hazard ratios (HRs) (95% confidence intervals [CIs]) of any CHIP and large CHIP were (1.21, 1.08–1.36) and (1.25, 1.09–1.43) for incident CVD, respectively. Significant associations between any CHIP and coronary heart disease (HR, 95%CI: 1.18, 1.03–1.36) and heart failure (1.73, 1.46–2.06) were observed, but not for stroke (1.14, 0.89–1.48). Gene-specific analyses suggested that the greatest association were for SF3B1 (HR, 95%CI: 2.50, 1.25–5.01) and TET2 (HR, 95%CI: 1.36, 1.07–1.77) with risk of CVD. There was no significant interaction between the four health indicators and CHIP in relation to incident CVD. Compared to patients without CHIP, those with any CHIP and ideal health indicators still exhibited significantly or nonsignificantly higher HRs (BMI: 1.18, 0.82–1.68; HbA1c: 1.12, 0.96–1.30; BP: 1.24, 1.03–1.49; LDL: 1.29, 1.09–1.53). Similar results were demonstrated using large CHIP. CHIP is independently associated with an increased risk of CVD in patients with diabetes, regardless of health indicator levels. Diabetic patients with CHIP but ideal health indicators still exhibited higher CVD risk compared with diabetic patients without CHIP.

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal role for CHIP in promoting AKI. Non-DNMT3A-CHIP was also associated with a nonresolving pattern of injury in patients with AKI. To gain mechanistic insight, we evaluated the role of Tet2-CHIP and Jak2V617F-CHIP in two mouse models of AKI. In both models, CHIP was associated with more severe AKI, greater renal proinflammatory macrophage infiltration and greater post-AKI kidney fibrosis. In summary, this work establishes CHIP as a genetic mechanism conferring impaired kidney function recovery after AKI via an aberrant inflammatory response mediated by renal macrophages. Clonal hematopoiesis, which increases with age and is implicated in a variety of age-related diseases, is shown here to be associated with a greater risk of acute kidney injury and worse outcome following injury, as demonstrated using multiple patient cohorts, Mendelian randomization analysis and mechanistic studies in mouse disease models.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored. METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr−/− mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell–derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow–derived macrophages, wild-type control, or cytokines IL-1β (interleukin 1β) or IL-6 (interleukin 6). RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr−/− mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1β or IL-6. CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) has been progressively established as a risk factor for cardiovascular disease and associated with worsened outcomes in patients with aortic valve stenosis (AVS). This cohort study aimed to evaluate the mutational landscape of CHIP and its' influence on clinical outcomes. METHODS 194 patients with AVS undergoing transcatheter aortic valve replacement (TAVR) were sequenced using a capture panel for multiple CH driver mutations and follow up conducted for three years. RESULTS We found high prevalences (77.8%) of a broad spectrum of CH-driver mutations across 38 genes, with 34% of patients fulfilling the diagnostic criteria for CHIP. Evaluating the impact of CHIP driver mutations on outcomes, the presence of CHIP was associated with mortality only when adjusting for confounding factors (HR: 2.143, 95% CI: 1.029-4.461, p = 0.042), while the presence of CH driver mutations at low VAF showed no association with mortality (p = 0.377). However, when excluding DNMT3A-CHIP, we found a significant association of CHIP with mortality in univariate (p = 0.022) and multivariable (HR: 2.976, 95% CI: 1.381-6.411, p = 0.005) analyses. CONCLUSIONS As the first study to evaluate a broad spectrum of CH driver mutations at all variant allele frequencies in the context of aortic valve stenosis, we found CHIP to be a frequent phenomenon and CH-driver mutations to be highly prevalent in patients with severe AVS. CHIP, other than DNMT3A-CHIP, was associated with increased mortality even after successful TAVR. The presence of CH driver mutations at low allele frequencies was not associated with mortality.

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cardiovascular diseases, but its association with venous thromboembolic events (VTE) is unclear. OBJECTIVES We investigated the association between CHIP and incident VTE in older adults and evaluated whether risk varies by CHIP driver gene. METHODS Participants from the community-based Atherosclerosis Risk in Communities (ARIC) Study without history of VTE or hematologic malignancies were included. Whole-exome sequencing from peripheral blood was used to ascertain CHIP (variant allele frequency [VAF] ≥2%) and common gene-specific CHIP subtypes (DNMT3A, TET2, and ASXL1). The primary outcome was incident VTE (adjudicated by experts from medical record review) defined as symptomatic and asymptomatic pulmonary embolism and lower extremity deep vein thrombosis. Multivariable Cox proportional hazards models were used to study the association between CHIP and VTE. RESULTS Of 3,980 participants included (median [25th-75th percentiles] age 75.0 [71.0-79.0] years), 2,359 (59.3%) were female, 1,621 (40.7%) were male, 890 (22.4%) identified as Black, and 3,090 (77.6%) identified as White; 985 (24.7%) had CHIP. Over median 7.1-year follow-up, VTE occurred in 44 (4.5%) CHIP carriers vs. 96 (3.2%) noncarriers (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.02-2.17, P=0.038). TET2 mutation was significantly associated with VTE risk (HR 2.25, 95% CI 1.27-4.00, P=0.006). CONCLUSIONS In this cohort study in older adults, we identified modestly increased risk of VTE in individuals with CHIP, mainly driven by TET2 mutation. Future research should explore the mechanisms driving these associations and assess potential therapeutic and preventive strategies.

No abstract available

BACKGROUND Patients with CKD are at higher risk of cardiovascular disease. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease in the general population, with a causal role observed in animal models. In the general population, the effect of CHIP is greater for somatic mutations in pre-defined CHIP driver genes other than DNMT3A (referred to as non-DNMT3A CHIP). We sought to assess the prospective association between CHIP and cardiovascular events in patients with CKD. METHODS CHIP was measured by high-depth targeted sequencing. The primary analysis tested the association of somatic mutations in non-DNMT3A CHIP driver genes with a composite cardiovascular disease endpoint of myocardial infarction, stroke, congestive heart failure, and peripheral artery disease in 5,043 patients with CKD in four prospective cohorts. Sensitivity analyses examined the effect of CHIP subtypes, race, baseline comorbidities, APOL1 risk alleles, and IL6R p.Asp358Ala genotype. RESULTS At baseline, patients had a mean age of 66 ± 12 years and eGFR of 43 ± 18 ml/min/1.73m2. CHIP was present in 24% of patients, with 13% of all patients carrying acquired non-DNMT3A mutations. Non-DNMT3A CHIP was associated with a 36% higher risk of the composite cardiovascular endpoint [95% confidence interval (CI), 6% - 76%]. Among composite components, non-DNMT3A CHIP was associated with a higher risk of stroke (HR 1.65; 95% CI 1.10 - 2.47). Baseline eGFR, diabetes status, or race did not alter the association of non-DNMT3A CHIP with cardiovascular risk. Those without genetically reduced interleukin-6 signaling (non-carriers of IL6R p.Asp358Ala) had worse disease (HR 1.46; 95% CI 1.17- 1.83, Psubgroup difference = 0.05). CONCLUSIONS In patients with CKD, non-DNMT3A CHIP was associated with cardiovascular disease with an effect size similar to that reported in the general population.

Clonal hematopoiesis of indeterminate potential (CHIP) might contribute to the pathogenesis of immune thrombocytopenia (ITP) through immune dysfunction or impairment of megakaryopoiesis and platelet formation. However, little is known about subsequent risk of ITP among individuals with CHIP.

Both clonal hematopoiesis of indeterminate potential (CHIP) and type 2 diabetes mellitus (T2DM) are conditions closely associated with advancing age. This study delves into the possible implications and prognostic significance of CHIP and T2DM in patients diagnosed with ST-segment elevation myocardial infarction (STEMI). Deep-targeted sequencing employing a unique molecular identifier (UMI) for the analysis of 42 CHIP mutations—achieving an impressive mean depth of coverage at 1000 × —was conducted on a cohort of 1430 patients diagnosed with acute myocardial infarction (473 patients with T2DM and 930 non-DM subjects). Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and T2DM was evaluated by the comparison of (i) the prevalence of CHIP mutations among individuals with diabetes versus those without, (ii) the clinical characteristics delineated by CHIP mutations within the cohort of diabetic patients and (iii) the prognostic significance and correlation of CHIP mutations with mortality rates in T2DM subjects. Furthermore, a two-sample bidirectional Mendelian randomization study was performed using genetic instruments from the genome-wide association study for TET2 mutation CH from the UK Biobank (UKB) (2041 cases,173,918 controls) to investigate the causal relationship with T2DM from the FinnGen consortium (65,085 cases and 335,112 controls), and vice versa. (i) Most commonly CHIP mutations exhibiting a variant allele fraction of ≥ 2.0% were identified in 50/473 (10.6%) patients with T2DM, demonstrating a greater prevalence compared to non-DM subjects [69/930 (7.4%); P < 0.05] across various age groups. (ii) After multivariable adjustment, the mortality of any CHIP mutations were 2.03-fold higher in DM [adjusted hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.07–3.84, P < 0.05]. (iii) In gene-specific analyses, TET2 somatic mutation presented the highest association with mortality among T2DM (adjusted HR 5.24; 95% CI 2.02–13.61, P = 0.001). ASXL1 CHIP mutation which displayed a striking correlation with cardiac death (HR: 3.14; 95% CI 1.24–7.93; P < 0.05) with consistent associations observed among T2DM subgroup (HR: 4.51; 95% CI 1.30–15.6; P < 0.05). (iv) The correlation between PCSK9 and the Tet2-CHIP mutation was observed in both the T2DM cohort (correlation = 0.1215, P = 0.011) and the overall enrolled cohort (correlation = 0.0578, P = 0.0382). (v) Bidirectional Mendelian randomization studies indicated that the development of T2DM increases the propensity for CHIP. However, CHIP does not subsequently accelerate the onset of T2DM. CHIP mutations, particularly TET2, are more prevalent in patients with T2DM compared to individuals without diabetes. The presence of these mutations is associated with adverse clinical outcomes, notably increased mortality rates. Moreover, bidirectional Mendelian randomization analyses provide supporting evidence for a potential causal relationship between TET2-related CHIP and the development of T2DM. Central Illustration: The association between clonal hematopoiesis of indeterminate potential (CHIP) and type 2 diabetes mellitus (T2DM): The prevalence of CHIP is notably higher in individuals with T2DM, as demonstrated in a prospective study within an Asian cohort of acute myocardial infarction (AMI). Furthermore, the predictive value of CHIP as a marker for poor clinical prognosis in T2DM has been assessed in this study. Mendelian randomization studies suggest that the development of T2DM may increase the propensity for CHIP, as indicated by findings from the UK Biobank and FinnGen consortium. T2DM, type 2 diabetes mellitus; CHIP, clonal haematopoiesis of indeterminate potential.

Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disease, often remaining asymptomatic until the thyroid is significantly affected. Clonal hematopoiesis of indeterminate potential (CHIP) has been reported to drive many inflammatory diseases and autoimmune diseases. The association between CHIP and AITD is scarcely reported. This study aims to investigate whether CHIP is associated with the risk of AITD. We conducted a prospective community-based cohort study at the UK Biobank. CHIP, defined as the exposure, was identified using whole-exome sequencing (WES) data. AITD was sourced from the inpatient hospitalization register, the death register, and the primary healthcare register. Cox regression models were utilized to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between CHIP and AITD. Next, we conducted a subgroup analysis to investigate the role of specific gene mutations (DNMT3A, TET2, ASXL1, PPM1D, SRSF2, and JAK2) in the investigated association. Finally, we assessed the association across small CHIP clones (variant allele frequency, VAF: 2–10%) and large CHIP clones (VAF ≥ 10%). All models were adjusted for sex, age, ethnicity, education, Townsend deprivation index, body mass index, smoking status, and drinking status. A total of 454,618 individuals were included in the final analysis. We identified 14,059 (3.1%) participants with CHIP. Compared with individuals without CHIP, those with CHIP were generally older and more likely to be smokers. Over a median follow-up of 12.7 years (interquartile range, IQR: 11.9–13.5), 21,708 cases with AITD were diagnosed. CHIP was associated with an increased risk of AITD (HR 1.11, 95% CI 1.03–1.19). Specifically, individuals with TET2-mutant CHIP (HR 1.23, 95% CI 1.07–1.41) had an elevated risk of AITD. A large CHIP clone (HR 1.17, 95% CI 1.08–1.27) was associated with an increased risk of AITD. Focusing on large CHIP clone, we also observed an association between TET2-mutant (HR 1.27, 95% CI 1.10–1.47) and ASXL1-mutant (HR 1.33, 95% CI 1.02–1.73) CHIP and risk of AITD. Individuals with CHIP were associated with a modestly increased risk of AITD, especially TET2-mutant CHIP. Future studies are needed to verify current findings and elaborate potential mechanisms.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the aging-related clonal expansion of preleukemic mutations in hematopoietic stem cells. While CHIP has been studied in cardiometabolic diseases (CMDs), its role in the long-term progression from the absence of CMD to the development of a single CMD, cardiometabolic multimorbidity (CMM), and eventual mortality remains uncertain. This study aimed to investigate the association between CHIP and gene-specific CHIP subtypes with the progression of CMD transitions. We included UK Biobank participants without CMD at baseline. The primary outcomes were the first CMD, CMM, and death. We evaluated associations between any CHIP (variant allele fraction [VAF] ≥ 2%), large CHIP (VAF ≥ 10%), and gene-specific CHIP subtypes (DNMT3 A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage genes], and SF3B1/SRSF2/U2 AF1 [spliceosome genes]) with CMD transitions via multistate model analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with age as the time scale, and adjusted for sex, race, Townsend Deprivation Index, body mass index (BMI), smoking, alcohol, physical activity, sleep duration, and hypertension. The study included 371,544 participants, with a mean age of 56.60 (± 8.03) years, and 44.2% of whom were male (CHIP: n = 11,570 [3.1%]; large CHIP: n = 7156 [1.9%]). During a median follow-up period of 14.49 years, 54,805 individuals developed at least one CMD, 8090 experienced CMM, and 26,218 died. In the fully adjusted multistate models, CHIP and large CHIP were associated with adjusted hazard ratios (HR) of 1.11 (95% CI 1.07–1.16) and 1.14 (95% CI 1.08–1.20), respectively, for transitioning from a CMD-free condition to a single CMD. The mortality risk associations were strongest, with adjusted HR of 1.45 (95% CI 1.36–1.55) and 1.64 (95% CI 1.52–1.77) for those without CMD, 1.39 (95% CI 1.26–1.54) and 1.59 (95% CI 1.41–1.79) for individuals with single CMD, and 1.58 (95% CI 1.31–1.91) and 1.61 (95% CI 1.29–2.02) for those with CMM. No significant association was observed with CMM development. Gene-specific analyses identified DNMT3 A, TET2, DNA damage genes, and spliceosome genes as the primary contributors to increased CMD risk. While CHIP showed no association with CMM progression, spliceosome genes were linked to a 1.72-fold higher risk (adjusted HR 1.72, 95% CI 1.14–2.59) of recurrent CMD events. All CHIP subtypes were strongly related to a heightened risk of mortality, with JAK2 presenting the highest adjusted odds ratio at 6.79 (95% CI 4.12–11.2). CHIP serves as an independent risk factor for transitioning to the first CMD incidence and for mortality but is not associated with CMM development. CHIP-targeted management may represent a promising strategy for the primary prevention of CMD and for reducing mortality risk.

Acute coronary syndrome (ACS) remains a leading global cause of mortality despite advances in revascularization therapies. This prospective cohort study investigated the synergistic prognostic impact of clonal hematopoiesis of indeterminate potential (CHIP) and atherogenic index of plasma (AIP) in 1396 ACS patients undergoing primary percutaneous coronary intervention at Fuwai Hospital (2017–2020). Using deep targeted sequencing (42 genes, median depth 14,219 ×), we identified CHIP mutations (VAF ≥ 2%) in 14.5% of participants, with DNMT3A (23.7%), TET2 (2.8%), and ASXL1 (1.9%) being most prevalent. High-AIP patients stratified by cutoff value were younger (57.8 vs. 63.2 years), had elevated hs-CRP (7.2 vs. 5.8 mg/L), and higher smoking rates, suggesting accelerated atherosclerosis. Multivariable Cox regression revealed that in patients with AIP ≥ cutoff, CHIP carriers exhibited significantly higher all-cause mortality, particularly for TET2 mutations (HR 5.20, CI 95%: 1.75–15.41; p = 0.003) and TET2/ASXL1 co-mutations (HR 5.5, CI 95%: 2.02–13.15; p = 0.001). Among individuals in the high AIP group, any CHIP (Fig. 3A, HR 2.38, 95% CI 1.18–4.81; P log-rank = 0.015) and common CHIP (Fig. 3B, HR 2.74, 95% CI 1.30–5.08; P log-rank = 0.008) mutation experienced a higher risk of mortality than individuals absence of CHIP mutation. These findings establish AIP as a critical modifier of CHIP-related cardiovascular risk, potentially through enhanced inflammatory pathways in younger ACS populations. The study highlights the clinical utility of combining lipid-based (AIP) and genetic (CHIP) biomarkers for precision prognostication, though validation in larger cohorts and mechanistic investigations of the AIP-CHIP interplay are warranted to guide targeted therapies. Key question: The potential interplay between atherogenic index of plasma -modulated metabolic dysregulation and Clonal hematopoiesis of indeterminate potential -associated cardiovascular risk remains unexplored. Key finding: Multivariable Cox regression revealed that in patients with AIP ≥ cutoff, CHIP carriers exhibited significantly higher all-cause mortality (adjusted HR 2.23, 95% CI 1.01–4.95; p = 0.048), particularly for TET2 mutations (HR 5.20, CI 95%: 1.75–15.41; p = 0.003) and TET2/ASXL1 co-mutations (HR 5.5, CI 95%: 2.02–13.15; p = 0.001). Among Individuals in the high AIP group, any CHIP (Fig. 3, HR 2.38, 95% CI 1.18–4.81; P log-rank = 0.015) and common CHIP (Fig. 3B, HR 2.74, 95% CI 1.30–5.08; P log-rank = 0.008) mutation experienced a higher risk of mortality than individuals absence of CHIP mutation. Take home message: These findings establish AIP as a critical modifier of CHIP-related cardiovascular risk, potentially through enhanced inflammatory pathways in younger ACS populations. The study highlights the clinical utility of combining lipid-based (AIP) and genetic (CHIP) biomarkers for precision prognostication, though validation in larger cohorts and mechanistic investigations of the AIP-CHIP interplay are warranted to guide targeted therapies. Central ilustration: The association between atherogenic index of plasma (AIP) and clonal hematopoiesis of indeterminate potential (CHIP) (Fuster et al. in Science 2017;355:842–7; Uddin et al. in Nat Commun 2022;13(1):5350; Wang et al. in Circ Res 2018;123(11):e35−e47).

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. CHIP has been associated with incident AKI and kidney function decline in the general population, particularly mutations in CHIP genes other than DNMT3A (termed non-DNMT3A CHIP). Prior studies of CHIP in individuals with CKD had limited sample sizes and conflicting findings. METHODS We examined CHIP and CKD progression in four CKD cohorts (N = 5,654): the Chronic Renal Insufficiency Cohort (CRIC), the African American Study of Kidney Disease (AASK), individuals with CKD from the BioVU biorepository, and the Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT).Primary outcomes were incident CKD progression (50% eGFR decline or kidney failure), and eGFR slope over time. In addition, kidney function and pathology were assessed in a Tet2-CHIP mouse model of CKD induced by dietary adenine. RESULTS Across all cohorts the average age was 66 ± 11 years, with an average baseline eGFR of 43 ± 15 ml/min/1.73m2, and 24% had CHIP. After meta-analysis, non-DNMT3A CHIP was associated with a 64% higher relative risk of incident CKD progression (hazard ratio [HR] 1.64; 95% confidence interval [CI], 1.00-2.68), with the strongest effect observed in individuals with baseline eGFR 30-60 ml/min/1.73m2 (HR 1.85, 95% CI: 1.18-2.90). Non-DNMT3A CHIP carriers also exhibited a faster eGFR decline (β, -0.62 ± 0.28 ml/min/1.73m2 per year; P = 0.03). In a dietary adenine mouse model of CKD, Tet2-CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. CONCLUSIONS Non-DNMT3A CHIP was associated with CKD progression among individuals with CKD. Further, Tet2-CHIP mouse models support a causal role in kidney injury.

Clonal hematopoiesis of indeterminate potential (CHIP) confers an increased risk of several chronic aging‐related diseases. Paradoxically, CHIP was associated with lower risk of dementia in recent studies.

PURPOSE Clonal hematopoiesis of indeterminate potential (CHIP) is a condition associated with increased risk of hematologic malignancies and cardiovascular diseases. While radiation therapy has been identified as a risk factor for CHIP, specific radiation factors that influence the development of CHIP remain unclear. METHODS AND MATERIALS We identified 489 cancer patients who underwent radiation therapy (RT) at least 6 months prior to blood samples deposited in an institutional biorepository. Patients with prior hematologic malignancy diagnosis or cytotoxic chemotherapy exposure were excluded. Targeted DNA sequencing of the blood samples was performed to detect mutations in CHIP-associated genes. CHIP prevalence was compared with a control cohort of 854 cancer patients without exposure to RT or chemotherapy. RT parameters, including dose, technique, and irradiated site, were characterized and examined for association with CHIP prevalence. RESULTS CHIP was detected in 23% of patients who received RT. The probability of CHIP was increased in patients who received RT compared to the patients who did not (odds ratio 1.49, 95% confidence interval 1.08-2.05), after adjusting for age, sex, race, smoking status, and metastatic disease status. The risk of CHIP positively correlated with the biologically equivalent dose (Pearson correlation coefficient r=0.64, p<0.001). CHIP was associated with stereotactic technique (OR 2.56, 95% CI 1.01-6.34) and more prevalent in patients with primary lung cancer and patients who received radiation to spine. We observed five cases of subsequent myelodysplastic syndrome and one case of subsequent acute myeloid leukemia in the RT cohort with a median interval of 6.3 years between RT and diagnosis, and one case of myelodysplastic syndrome in the control cohort, 7.5 years after blood sample collection. CONCLUSIONS In this cohort study, prior radiation therapy was associated with an increased risk of clonal hematopoiesis, particularly among patients receiving higher biologically equivalent radiation doses, stereotactic techniques, or treatment to the spine.

No abstract available

Clonal hematopoiesis of indeterminate potential (CHIP) is a predisposing condition to lymphoma development. CHIP carrying mutations that are recurrently found in lymphomas are designated as L‐CHIP. We presume that bone marrow‐derived L‐CHIP populations are able to expand and manifest in peripheral lymphoid tissues, where they could hence be called L‐CHIP tissue‐equivalents. There, they may proliferate and foster unexplained follicular hyperplasias, and, thus, potentially represent an early precursor of lymphoma. Analogously, we hypothesize that certain germline‐derived mutations lead to lymphoproliferations (germline‐derived lymphoproliferations) in otherwise healthy individuals. We collected seven exceptional cases of symptomatic nodal and extranodal lymphoid hyperplasias, which were all morphologically suspicious and displayed somatic and/or germline‐derived mutations recurrently found in B‐cell lymphomas. One patient developed follicular lymphoma after 8 years carrying the same non‐productive immunoglobulin rearrangement detected in the initial biopsy. L‐CHIP tissue‐equivalents and germline‐derived lymphoproliferations potentially represent first steps in lymphomagenesis and knowledge about their existence might be of diagnostic utility in challenging cases of (atypical) lymphoproliferations. With histology, immunohistochemistry, and molecular testing, such lesions can be identified in situ.

Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) have been linked to cardiovascular disease (CVD), with DNA methyltransferase 3A (DNMT3A) being the most commonly mutated gene. (Jaiswal et al. 2017; Abplanalp et al. 2021) We generated a genome-edited human induced pluripotent stem cell (hiPSC) line with a homozygous knock-out (KO) of DNMT3A, to mimic loss-of-function mutations, and an isogenic mock-treated control line (mock ctrl). For quality control, we tested the pluripotency of these hiPSC lines and their ability to differentiate into the three germ layers. The generation of these cell lines enables the analysis of cellular pathomechanisms of DNMT3A-related, CHIP-associated CVDs.

lonal hematopoiesis of indeterminate potential (CHIP) is caused by acquired mutations in hematopoietic stem cells that yield clonal progeny of mutant leukocytes. CHIP is rarely present in peripheral blood before 50 years of age, but thereafter, its incidence rises rapidly, affecting >10% to 20% of the population aged 70 to 80 years. 1 Blood pressure levels also start to increase steeply after 50 years of age. Although CHIP and hypertension are both age-related cardiovascular risk factors, their interplay remains unclear. Our aim was to examine the association of CHIP with incident hypertension

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. OBJECTIVES This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. METHODS Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. RESULTS Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). CONCLUSIONS CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is commonly diagnosed at a young age, often in individuals in their 20s. However, with increasing life expectancy and advancements in diagnostic techniques, the incidence of HCM being diagnosed in older individuals is rising. Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a common age-related condition resulting from the expansion of hematopoietic stem cells due to mutations. In this study, we analyzed the correlation between HCM and CHIP and their clinical characteristics. A study was conducted on 66 HCM patients recruited from a tertiary hospital in Korea, from November 2021 to January 2024. The patients' demographic data, echocardiographic parameters and HCMP patterns were collected. The HCM patterns were analyzed based on Helmy's classification, and Pattern 4 was classified as Pure apical. Furthermore, the genomic DNA related to HCM in those patients was extracted and sequenced. Analysis for Clonal Hematopoiesis of Indeterminate Potential (CHIP) mutation was also conducted. CHIP mutation analysis was performed on 66 patients, and mutation was detected in 31 of them. The most common variant was DNMT3A(33%), followed by TET2 and ASXL. Compared to CHIP (-) patients, CHIP (+) patients were significantly older on average (60.31±10.3 vs 67.1±9.3, P-value=0.07) and had a significantly higher average age at diagnosis(55.49±12.1 vs 61.06±10.1, P-value=0.049). Additionally, they had a significantly lower BMI(26.1±3.2 vs 24.5±3.0, p value=0.037) and higher prior stroke(5.7% vs 25.8%, P-value=0.037). In echocardiographic findings, the deceleration time(DT) was significantly shorter(223.7±59.8 vs 193.9±44.4, P-value=0.027) in CHIP (+) patients. Although a higher proportion of CHIP (+) patients had the Pure apical type compared to CHIP (-) patients, this difference was not statistically significant (34.3% vs 54.8%, P-value 0.093). Based on genomic DNA analysis, patients were divided into those with Pathogenic/Likely Pathogenic (P/LP) variants and those without. Among P/LP(-) patients, groups were further divided based on the presence or absence of CHIP mutation. Analyzing age and age at diagnosis among these three groups revealed no significant differences. CHIP mutations exhibit a prevalence of approximately 10% in individuals over the age of 70. In our pilot study, CHIP (+) was found in 31 out of 66 patients (47%), which is a higher proportion than in the general population. The CHIP (+) group was, on average, older and had an older age at diagnosis. They also had a higher incidence of stroke, shorter Deceleration Time, and lower BMI. While the analysis of HCM patterns showed that the Pure apical type was more common in the CHIP (+) group, this difference was not statistically significant. Characteristics of HCM patients

Clonal Hematopoiesis of Indeterminate Potential (CHIP) is a phenomenon of elevated somatic carcinogenic mutations (measured by variant allele fraction (VAF)) with a paradoxical absence of cancerous phenotypes. CHIP risk increases with age, and is a significant risk factor for future blood cancers and cardiovascular disease, even when controlling for age. Recent analyses show a protective association between CHIP and Alzheimer's disease (AD) using longitudinal and Mendelian Randomization (MR) analyses, which is an unusual finding given age's strong impact on both CHIP and AD.

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an unrecognized, potent, age-related risk factor for atherosclerosis and cardiovascular complications. The presence of CHIP may contribute to the risk of atrial fibrillation (AF) and heart failure through its association with inflammation and cardiac remodelling. However, few studies have focused on the impact of clonal hematopoiesis on cardiac remodelling in these conditions. We hypothesized that patients with AF might have a distinct pattern as assessed with myocardial strain of the 4-cardiac chambers according to the presence of clonal haematopoiesis (CH). We retrospectively analysed 94 patients hospitalized for AF. All patients had clinical, biologic evaluation with dedicated analysis of CH, defined by the presence of mutation of variant allele frequency, VAF >1%. Using echocardiography and speckle tracking, we performed four-cardiac chambers strain analysis (left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA)) were analysed off-line using Ultrasound Workspace software, Philips (Figure 1). Patients were divided into two groups according to the presence (CH +, n=45) or absence (CH -, n=49) of clonality. Median age of the population was 69 (63-76) years, and 52 (55%) patients were male. CH+ patients, in comparison with CH - patients, had more frequently persistent AF (32(84%) versus 29(64%), p=0.049), and more frequently history of coronary artery stenting (4(8.9%) versus 0(0%). No significant differences were observed between CH + and CH – patients, concerning the history of hypertension (21(47%) versus 26(53%), p=0.54), diabetes (5(11%) versus 7(14%), p=0.64), and tobacco (22(49%) versus 20(41%), p=0.43). We found no significant differences in 2D TTE measurements and in global longitudinal LV, LA, RA and RV strains, between CH + and CH -. In this preliminary work, clonal hematopoiesis of indeterminate potential (CHIP) did not seem to induce cardiac remodeling in AF. Further investigations are warranted in larger clinical studies and cohorts to evaluate the determinants of cardiac remodeling in AF patients and its possible implication.  

Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Clonal hematopoiesis of indeterminate potential (CHIP) has been implicated in atherosclerosis through inflammation and immune dysregulation. CHIP mutations in genes such as DNMT3A, JAK2, ASXL1, and TET2 have been associated with an increased risk of cardiovascular events. However, their exact contribution to CAD pathogenesis remains incompletely understood. This study aims to investigate the prevalence of CHIP mutations in CAD patients and assess their potential association with disease severity and clinical outcomes. A case-control study was conducted with 131 CAD patients and 131 age- and gender-matched controls. DNA was extracted from peripheral blood samples and analyzed for CHIP mutations using polymerase chain reaction (PCR) and Sanger sequencing. Key biochemical markers, including hemoglobin, lipid profiles, and inflammatory markers such as high-sensitivity C-reactive protein (hsCRP) and lipoprotein(a) [Lp(a)], were measured. In-silico analysis was performed to explore molecular interactions among DNMT3A, JAK2, ASXL1, and TET2. 1. Mutation Analysis: Two missense mutations in DNMT3A were identified in CAD patients, while no mutations were detected in controls. 2. Biochemical Parameters: CAD patients exhibited significantly lower hemoglobin levels (12.4 ± 2.4 g/dL) compared to controls (13.9 ± 1.7 g/dL, p < 0.05). 3. Lipid Profile: Lower total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were observed in CAD patients. 4. Renal Function: Higher blood urea nitrogen (BUN), creatinine, and uric acid levels were noted in CAD patients. 5. Inflammatory Markers: Elevated hsCRP and Lp(a) levels correlated with the presence of CHIP mutations, suggesting an inflammatory link between CHIP and CAD progression. 6. In-Silico Analysis: Molecular interaction studies indicated a potential regulatory network among DNMT3A, TET2, JAK2, and ASXL1, which may contribute to CAD pathogenesis. This study provides evidence supporting the role of CHIP mutations, particularly DNMT3A, in CAD pathogenesis. The findings highlight the potential of CHIP mutations as biomarkers for CAD risk assessment and suggest that anti-inflammatory interventions targeting CHIP-related pathways could be explored as therapeutic strategies. Future Direction: Further large-scale studies using next-generation sequencing (NGS) are needed to comprehensively map CHIP mutations and validate their association with CAD outcomes. Prospective trials evaluating anti-inflammatory therapies such as colchicine in CHIP-positive patients could provide insights into novel treatment strategies.Interaction analysis of the genes

Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of blood stem cells with leukemia-associated mutations. Mounting evidence suggests that certain CHIP variants contribute to atherosclerosis and heart failure through proinflammatory and immune-related pathways; however, CHIP’s role in immune-mediated cardiac conditions, including myocarditis and pericarditis, remains unclear. To test the associations of CHIP and gene-specific CHIP subtypes with new-onset myocarditis and pericarditis. This study included UK Biobank participants with whole exome sequencing data and no history of cardiovascular disease at baseline. The primary study outcome was a composite of myocarditis and pericarditis ascertained through linkage to inpatient health records. Secondary analyses tested myocarditis and pericarditis as separate outcomes. Associations of any CHIP (variant allele fraction [VAF] ≥ 2%), large CHIP (VAF ≥10%), and the most common gene-specific CHIP subtypes (CHIP driven by mutations in DNMT3A or TET2) with incident myocarditis and pericarditis were evaluated using unadjusted cumulative incidence plots and multivariable-adjusted Cox regression models. This study included 335,907 participants with whole exome sequencing and no cardiovascular disease at baseline (mean age, 56.1 [SD, 8.1] years; female: n=185,811 [55.3%]), of whom 11,195 (3.3%) were CHIP carriers. Incident myocarditis and pericarditis events occurred in 155 (0.05%) and 182 (0.05%) participants, respectively, over a mean follow-up period of 13.6 (SD, 0.8) years. Unadjusted analyses revealed a higher incidence of the primary composite outcome of myocarditis and pericarditis, as well as these outcomes separately, in CHIP carriers versus non-carriers (Figure 1). The presence of CHIP was associated with a multivariable-adjusted hazard ratio of 1.67 (95% CI, 1.06-2.63; P=2.8×10-2) for the primary composite outcome, with a similar magnitude of effect observed for myocarditis and pericarditis separately. Excess risk was even more pronounced among individuals carrying large CHIP clones, those with DNMT3A mutations, and those with TET2 mutations, who had a two- to three-fold higher risk of myocarditis and pericarditis compared to non-carriers (adjusted hazard ratios: 1.99 [95% CI, 1.20-3.30], P=7.7×10-3 for large CHIP; 2.07 [95% CI, 1.23-3.49], P=6.1×10-3 for DNMT3A mutations; and 3.36 [95% CI, 1.49-7.57], P=3.4×10-3 for TET2 mutations) (Figure 2). CHIP represents a strong risk factor for the development of myocarditis and pericarditis among midlife adults. Future work should evaluate the actionability of CHIP-related pathways to prevent and treat these immune-mediated cardiac conditions.  

Abstract Background and Aims Clonal hematopoiesis of indeterminate potential (CHIP) has recently been recognized as a significant risk factor for various non-hematologic conditions, particularly cardiovascular diseases. However, the relationship between CHIP and atrial fibrillation (AF) remains underexplored to date. Given the conflicting findings in recent studies, the present meta-analysis aimed to assess the association between CHIP and the incidence or recurrence of AF. Methods Medline, Cochrane Library and Scopus were searched until October 27, 2024. Triple-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using restricted maximum likelihood random-effects meta-analysis. Results Four studies comprising a total of 801,085 participants were included. Over a median follow-up period of 9 years, participants with any CHIP [variant allele fraction (VAF) ≥ 2%] exhibited a significantly elevated risk of developing incident or recurrent AF compared to those in the non-CHIP group (hazard ratio [HR] = 1.12; 95% confidence interval [CI] = [0.07 to 1.17], P < 0.0001; I² = 3%, heterogeneity P = 0.38). The presence of any CHIP was associated with a markedly increased risk for both incident and recurrent AF when these outcomes were analyzed separately. Furthermore, large CHIP (VAF ≥ 10%) was correlated with a heightened risk of incident AF, suggesting a potential dose-response relationship. Leave-one-out sensitivity analyses identified no evidence of outliers. Conclusions CHIP is associated with increased risk of incident or recurrent AF. Further research is required to clarify the mechanisms underlying the observed association and to explore interventions aimed at mitigating this risk.

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging risk factor for cardiovascular diseases. Genetic IL (interleukin)-6 signaling deficiency reduced cardiovascular disease risk in CHIP carriers. However, the association between CHIP and incident abdominal aortic aneurysm (AAA) and whether IL-6 signaling inhibition attenuates AAA risk among individuals with CHIP remained unclear. METHODS Participants without prevalent AAA from the UK Biobank were included. The associations of any CHIP (variant allele fraction, ≥2%), large CHIP (variant allele fraction, ≥10%), and gene-specific CHIP subtypes with incident AAA were investigated. The protection role of IL6R p.Asp358Ala, a genetic proxy for IL-6 deficiency, was tested after stratification by CHIP status. Furthermore, the interaction and joint effects of CHIP and genetic susceptibility on AAA risk were tested. RESULTS This study included 425 211 participants. Any CHIP and large CHIP was identified in 13 768 (3.2%) and 8576 (2.0%) participants, respectively. CHIP was associated with an increased risk of incident AAA (hazard ratio [HR], 1.21 [95% CI, 1.01-1.44]; P=0.034), with large CHIP clones exhibiting greater effect size (HR, 1.35 [95% CI, 1.10-1.66]; P=0.0045). Driver gene-specific analyses revealed that ASXL1-mediated CHIP exerted the strongest effect size on AAA risk (HR, 2.10 [95% CI, 1.54-2.88]; P<0.001). The presence of 2 IL6R p.Asp358Ala alleles attenuated the risk of AAA in large CHIP carriers (HR, 0.48 [95% CI, 0.23-0.99]; P=0.046). In the joint analysis, participants with CHIP and high genetic risk had a higher risk of developing AAA than those without CHIP and with low genetic risk (HR, 2.15 [95% CI, 1.63-2.85]; P<0.001). CONCLUSIONS CHIP is associated with an increased risk of AAA. Genetic IL-6 signaling deficiency attenuates the risk of AAA in large CHIP carriers. CHIP may serve as an attractive target for the prevention and treatment of AAA.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) was recently shown to be an independent risk factor for immune checkpoint inhibitor (ICI)-associated myocarditis. However, the mechanisms by which CHIP may contribute to immune dysregulation in this context remain poorly understood. Research Questions: How does CHIP contribute to immune dysregulation in cancer patients receiving ICIs, and what cytokine-producing cell types and pathways drive CHIP-associated inflammation? Methods: To investigate this, we implemented the CellChat framework to single-cell RNA sequencing (scRNA-seq) data in order to infer and compare cell-cell communication networks. We analyzed scRNA-seq data from six post-ICI myocarditis patients, three of whom were CHIP-positive and three CHIP-negative from Yale. Using CellChat, we constructed condition-specific intercellular signaling networks and compared overall signaling activity, communication strength, and pathway usage across groups. We further validated the findings with two other cell-cell interaction analysis tools, DominoSignal and CellPhoneDB. Results: CHIP-positive samples exhibited a higher number (3440 vs 2466 CHIP vs no CHIP) and strength of ligand-receptor interactions compared to CHIP-negative samples (110 vs 75, CHIP vs no CHIP), indicating globally elevated intercellular signaling (Figure 1). Network and heatmap visualizations revealed increased cell-cell communication in CHIP positive patients compared to CHIP negative patients particularly among immune cell types, including monocytes, platelets, plasmacytoid dendritic cells, and naive B cells. Directional analysis showed enhanced outgoing signals from naive B cells and increased incoming signals to macrophages and plasmacytoid dendritic cells in CHIP-positive samples. Of note, increased platelet interactions with native CD4 and CD8 T cells were noted. Pathway-level analysis highlighted upregulation of pro-inflammatory and pro-platelet activation signaling, including TNF, CXCL, CD30, and CD40 (Figure 2). Conclusion: These findings suggest that CHIP is associated with a pro-inflammatory signaling environment that contributes to ICI myocarditis. These findings support its potential as a biomarker for risk stratification and as a target for pathway-specific anti-inflammatory therapies. For future directions, these results will be validated with external ICI myocarditis cohorts.

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Summary Background Cross sectional studies have demonstrated patients with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of developing multiple adverse outcomes, including cytopenia and myeloid neoplasm (MN). One prior study suggests cytopenia or cytosis is a required intermediate step in disease progression from CHIP to MN. Methods We analyzed genomic sequencing data from the NIH All of Us Research Program, Vanderbilt’s BioVU repository, and UK Biobank participants (N = 805,249). The study period ranged from 1 January 2006 to 31 December 2023. Genetic mutations, demographic data, laboratory values, and MN outcomes were used to create a case-control study to estimate the risk of incident cytopenia and MN among cases with CHIP and matched controls without CHIP. Findings After applying inclusion and exclusion criteria, the study cohort contained 9374 cases with CHIP and 24,749 matched controls without CHIP. Among the 34,123 participants, 190 (0.56%) developed incident cases of MN and 4151 (12.1%) developed an incident cytopenia. Individuals with CHIP at enrollment who subsequently developed a cytopenia progressed to MN at a rate of 0.5% per year, compared to 0.05% per year for those with CHIP and normal cell counts. Longitudinal analysis across three cohorts demonstrated an increased risk of cytopenia in CHIP patients and identified those at the highest risk of progression. Cytopenia risk factors included smoking (HR = 1.17, 95% CI: [1.05–1.32], P = 5.87 × 10−3), male sex (HR = 1.45, 95% CI: [1.30–1.62], P = 2.17 × 10−11), variant allele frequency ≥0.20 (HR = 1.36, 95% CI: [1.21–1.54], P = 7.56 × 10−7), age ≥65 (HR = 1.41, 95% CI: [1.25–1.57], P = 3.98 × 10−9), mean corpuscular volume ≥100 fL (HR = 2.12, 95% CI: [1.68–2.68], P = 2.58 × 10−10), red cell distribution width ≥15% (HR = 2.59, 95% CI: [2.26–2.98], P = 1.14 × 10−40), mutations in high-risk CHIP genes (HR = 1.48, 95% CI: [1.26–1.75], P = 2.39 × 10−6), and ≥2 CHIP mutations (HR = 1.95, 95% CI: [1.61–2.36], P = 9.73 × 10−12). Interpretation Longitudinal analysis across three large cohorts found that it is rare for patients with CHIP to develop MN without first developing cytopenia. The risk for MN among patients with CHIP resides almost entirely among those with cytopenia. These findings suggest that cytopenia is a critical step in progression from CHIP to MN, underscoring its utility as an endpoint in cancer prevention trials for CHIP patients. Funding 10.13039/100000002National Institutes of Health, 10.13039/100000861Burroughs Wellcome Fund, 10.13039/100008884Edward P. Evans Foundation, 10.13039/100000875Pew Charitable Trusts, 10.13039/100001353Alexander and Margaret Stewart Trust, Beverly and George Rawlings Directorship.

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1–5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6–10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34–3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection. In a prospective cohort study, HIV-positive participants have a higher incidence of clonal hematopoiesis than HIV-negative ones, implicating clonal hematopoiesis in the increased risks of individuals with HIV for malignancy and cardiovascular disease.

Summary While HIV infection and clonal hematopoiesis (CH) have been linked with inflammatory dysregulation and an increased risk of aging-related comorbidities, their relationship with clinical geriatric syndromes has not been well defined. In the Age-related Clonal Haematopoiesis in an HIV Evaluation Cohort (ARCHIVE) study (NCT04641013), we measure associations between HIV and CH and geriatric syndromes. Of 345 participants (176 with HIV and 169 without HIV), 23% had at least one mutation associated with CH: 27% with HIV and 18% without HIV (p = 0.048). In adjusted analyses, HIV infection is independently associated with increased phenotypic age acceleration (coefficient 1.73, 95% confidence interval [CI] 0.3, 3.16) and CH is independently associated with being frail (vs. pre-frail/robust; odds ratio 2.38, 95% CI 1.01, 5.67) and with having reduced quality of life (coefficient −2.18, 95% CI −3.92, −0.44). Our findings suggest that HIV is associated with increased biological age and that CH may be used as a biomarker for adverse geriatric outcomes.

Age-related clonal hematopoiesis (ARCH) is associated with aging and can easily lead to malignant hematological or cardiovascular disease. DNA (cytosine-5)-methyltransferase 3A (DNMT3A) fulfils a variety of different functions during the aging process and is frequently mutated in ARCH and subsequent hematological malignancies. However, the specific molecular mechanism by which DNMT3A influences ARCH is unclear. This project first confirmed that DNMT3A mutations in hematopoietic stem and progenitor cells (HSPCs) were present in clinical samples from a large cohort of healthy volunteers. Secondly, we constructed a Dnmt3a R878H knock-in mouse model and found that Dnmt3a R878H mutation could induce hematopoietic cloning abnormalities in mice over a year later, mainly manifested in the active proliferation of HSPCs, deviations in the functional differentiation trajectory, and micro-environment disorder of immunity. Then, we applied high-throughput chromosomal capture (Hi-C) and single-cell RNA sequencing to explore the effects of aging-associated DNMT3A mutations in HSPCs, together with chromosome spatial structure change and transcriptional regulation and an in-depth investigation of the downstream molecular effects of the DNMT3A mutation on ARCH and the regulation of homeostasis and associated factors in immune cells, providing a new foundation for the early diagnosis and prevention of blood-related diseases induced by clonal hematopoiesis. Single-cell sequencing has suggested the existence of significant heterogeneity among hematopoietic stem cells, and that Dnmt3a mutations can regulate histone methylation modifications in hematopoietic stem and progenitor cells. Hi-C sequencing has revealed that in hematopoietic stem and progenitor cells, the overall chromatin conformation undergoes relatively subtle changes. However, closer examination of the inter-chromosomal interactions shows that the primary alterations occur between chromosomes 12 and 19. Utilizing advanced bioinformatic techniques to analyze differential Topologically Associating Domains (TADs) and chromatin loops, we identified significant differences in the spatial organization strength located specifically on chromosome 19. This finding suggests that, despite the overall stability of the chromatin landscape, specific regions such as those on chromosome 19 undergo more pronounced structural rearrangements, potentially impacting gene regulation and cellular function in these critical hematopoietic cell populations. Combining the preliminary Hi-C analysis results from ARCH mice, we identified Apobec3 as one of the significantly dysregulated genes following Dnmt3a mutation. Given the established roles of Apobec3 in DNA repair and RNA editing, our RNA sequencing GSEA analysis in mice suggests that the DNA damage repair pathway is markedly enhanced in Dnmt3a-mutated hematopoietic stem and progenitor cells as well as granulomonocytic cells. This indicates that Dnmt3a mutation may induce increased DNA damage, subsequently activating the DNA repair pathway. Within the DNA repair-related gene clusters, we observed that the expression of Atm gene and protein is significantly lower in mutant mice compared to wild-type mice, suggesting a partial blockade of cellular repair function in mutant mice. Further validation using patient bone marrow cells and 293 cells overexpressing mutated DNMT3A and APOBEC3F revealed that, among the DNA repair-related gene clusters, all genes except ATM showed increased expression, while ATM expression was notably decreased. Additionally, comet assay studies demonstrated a pronounced tailing phenomenon in cells harboring the mutation. Exome sequencing of mice revealed that with enhanced Apobec gene expression in mutant mice, there was a significant increase in the number of copy number variations (CNVs) and single nucleotide variations (SNVs). Collectively, these results suggest that Dnmt3a mutation can induce DNA/RNA damage through Apobec3, leading to secondary genetic mutations by interfering with the cellular repair machinery. The compromised repair capacity in turn facilitates the accumulation of additional genetic alterations, underscoring the complex interplay between epigenetic regulators, DNA damage, and repair pathways in the context of hematopoietic malignancies.

No abstract available

Clonal hematopoiesis (CH) is an age-related condition characterized by clonal expansion of hematopoietic stem cells (HSCs) bearing somatic mutations in CH-defined genes. Different mutation combinations contribute concurrently or mutually exclusively to CH progression and disease subtypes. SRSF2 is among the most frequently mutated splicing factors, with the P95 hotspot driving aberrant splicing and predicting poor prognosis in hematologic malignancies. While SRSF2P95H recapitulates myelodysplastic syndromes (MDS) in mice and has been studied with co-mutations in IDH1/2, ASXL1, RUNX1, TET2 and JAK2, its interplay with RAS signaling remains unclear. NF1, a negative RAS regulator and tumor suppressor, when deleted in hematopoietic cells, causes progressive myeloproliferative neoplasms in mice. To assess the combinatorial impacts of SRSF2 and NF1, we retrospectively analyzed patients from our hospital over five years. Patients harboring both SRSF2P95H and NF1 mutations (SN) were compared to those with SRSF2P95H instead of NF1 (S), or NF1 without SRSF2P95H (N). SN patients were more frequently diagnosed with myeloid malignancies (96.2%), spanning AML, MDS/MPN, MPN, MDS, with one T-ALL case. Elevated WBC, neutrophil, and monocyte counts also suggested enhanced myeloid skewing in SN individuals. We modeled this in vivo by generating mice with hematopoietic-specific Srsf2P95H mutation and/or Nf1 deletion: wildtype (WT), Srsf2P95H alone (S), Nf1 homozygous deletion (NN), and the double mutant (SNN). Compared to S and NN mice, SNN exhibited progressive neutrophilia and lymphopenia in peripheral blood (PB). PB smears showed increased hyposegmented neutrophils. Bone marrow (BM) flow cytometry revealed expansions of LKS+, HSC, MPP1, CMP, PreGM, Mac-1+ cells and Mac-1+ Ly6G+ neutrophils, partially at the expense of CLP proportion and B-lineage maturation. In BM transplantation (BMT) assays, SNN recipients exhibited marked HSPCs reduction despite lower donor chimerism; Mac-1+ cells maintained advantageous expansion. Gene set enrichment analysis (GSEA) revealed upregulation of RNA splicing, apoptosis, and notably, JAK-STAT pathways (STAT3, STAT5, and phosphorylation). Western blotting confirmed STAT3/5 hyperphosphorylation. Differential gene expression analysis showed increased Il6ra, Jak2, Ccnd1, Ccnd2 and other JAK-STAT components. Splicing analysis confirmed known Ezh2 poison exon inclusion, revealed aberrant skipping of Jak2 exons 13 and 14, and identified a mis-splicing landscape of JAK-STAT genes in SNN HSCs. We hypothesized that under RAS hyperactivation, Srsf2P95H amplifies JAK-STAT signaling via mis-splicing of its key components. To validate this, we treated BMT mice with DMSO, ruxolitinib (RUX) or CTX-712 (CTX). RUX is a classic selective JAK inhibitor; CTX targets CDC2-like kinases to suppress SRSF2 phosphorylation. Developed by Seishi Ogawa's team in 2017, CTX is currently in global phase I/II trials. Unexpectedly, RUX significantly restored donor chimerism and HSC frequency with reductions in Mac-1+ cells and neutrophils to levels seen in CTX-treated SNN or DMSO-treated WT. Colony formation assays confirmed improved HSPC output and reduced CFU-GM bias. GSEA of RUX-treated SNN HSCs showed downregulation of IL6-JAK-STAT3 signaling and upregulation of DNA repair. Since CH prevalence rises with age and SRSF2 mutations occur more frequently in the elderly, we analyzed the correlation between co-mutation and aging. SN patients were diagnosed at an older age than SRSF2-WT ones. In mice, SNN HSCs showed significant downregulation of focal adhesion, a hallmark of HSC senescence. Whole-exome sequencing revealed that aged SN/SNN mice accumulated more somatic mutations, consistent with human CH. Interestingly, we discovered a novel Jak2 exon 13 missense mutation, validated by Sanger sequencing. Taken together, we demonstrate that under Nf1 deficiency, Srsf2P95H impairs HSC function and exacerbates myeloid-biased hematopoiesis by augmenting JAK-STAT signaling, which can be rescued by JAK inhibition. Our findings elucidate the synergistic effects of Srsf2P95H and Nf1 loss in CH progression, uncovering an unanticipated JAK-STAT-dependent mechanism mediated by Srsf2P95H. Furthermore, we highlight a conserved, age-related pathophysiological trajectory of CH between humans and mice, providing a preclinical model to dissect molecular interactions in age-related CH and to support therapeutic development in hematologic malignancies.

Background The gain of mutations with a competitive advantage in hematopoietic cells of healthy individuals is common with aging and termed clonal hematopoiesis of indeterminate potential (CHIP). Through sequencing studies we detected CHIP related mutants in chronic myeloid leukemia (CML) patients in deep molecular response. CHIP mutants may provide a selective growth advantage to non-leukemic cells, driving their clonal expansion in remission and potentially influencing treatment-free remission (TFR) if CHIP clones outcompete an emerging BCR:: ABL1 clone. Aim To determine if CHIP mutants detected at the time of stopping tyrosine kinase inhibitor (TKI) therapy could influence achievement of TFR. Methods An RNA-based sequencing method targeting 17 of the most frequently mutated CHIP genes was developed and applied to blood samples of 150 patients who attempted TFR. The median follow up of patients in TFR was 71 months. CHIP mutants met strict criteria for pathogenicity based on their potential to confer growth and survival advantages, i.e. the same criteria as cancer driver mutations. Variant allele frequency (VAF) of ≥0.4% was reproducibly detected. CHIP at the time of cessation, termed CHIP TOC, was defined as 1) ≥1 CHIP mutant with VAF ≥2.0% (n=30 patients) or 2) a novel criterion for patients with multiple CHIP mutants where the combined VAF was ≥2.0% (n=7). Overall, 25/37 patients (68%) with CHIP TOC had multiple mutations, range 2-7. Results CHIP TOC was detected in 37/150 patients (25%). The average age of patients with CHIP TOC was 66.3 years vs 58.0 for those without, P=.0004, which is consistent with the age related nature of CHIP. No patient aged <40 had CHIP TOC, whereas 44% of patients ≥70 had CHIP TOC. Twelve genes were mutated and the most frequent were TET2, DNMT3A, ASXL1 and PPM1D. The overall probability of TFR was 60.4% at 12 months and 53.0% at 84 months. CHIP TOC was associated with TFR. At 12 months, 83.6% of patients with CHIP TOC maintained TFR versus 52.9% of patients without CHIP TOC, P=.002. At 84 months, 62.9% of patients with CHIP TOC maintained TFR versus 49.6% of patients without CHIP TOC, P=.014. We previously demonstrated that e13a2 transcripts and a slow initial decline of BCR:: ABL1 after starting frontline TKI therapy, measured as the number of days over which BCR:: ABL1 halved, were our strongest predictors of relapse. Prognostic factors for the achievement of TFR at 12 and 84 months were examined in multivariable analysis. Candidate prognostic factors were CHIP TOC, BCR:: ABL1 halving time, BCR:: ABL1 transcript type, age at diagnosis, gender, duration of MR4.5 and time on TKI before TKI stop. The independent predictors of TFR at 12 and 84 months were the presence of CHIP TOC at TKI stop, a shorter BCR:: ABL1 halving time (indicating a more rapid initial BCR:: ABL1 decline) and the e14a2 (plus e14a2/e13a2) BCR:: ABL1 transcript type (Table 1). The rate of late relapse, defined as loss of MMR >12 months after cessation, was higher in patients with CHIP TOC. Overall, 85 patients had TFR at 12 months and late relapse occurred in 8. A landmark analysis demonstrated that the probability of maintaining TFR at 84 months for these 85 patients was 93.8% for those without CHIP TOC (n=57) and 75.2% for those with CHIP TOC (n=28), P=.007. The only variable associated with late relapse among the patients with CHIP TOC was fluctuation of BCR:: ABL1 within the first 12 months after cessation, defined as irregular rise and fall comprising 2 consecutive BCR:: ABL1 ratios with loss of MR4.5, or a single loss of MR4. Overall, 13 patients had fluctuation within the first 12 months and 5 of these had late relapse. All 5 had CHIP TOC. Patients with CHIP TOC and stable MR4.5 by 12 months had a 93.8% probability of TFR at 84 months (Table 2). Conclusion The presence of CHIP TOC at TKI cessation, a shorter BCR:: ABL1 halving time and e14a2 BCR:: ABL1 transcripts were independent predictors of TFR at 12 and 84 months. Delayed loss of MMR that occurred for a minority of patients with CHIP TOC may be associated with competition between CHIP clones and a residual leukemic clone. These patients had fluctuating BCR:: ABL1 over the first 12 months after cessation and prior to late relapse. Novel strategies may be warranted to reduce the risk of late relapse for these patients. Patients who sustained TFR by 12 months in stable MR4.5 had a reassuringly low risk of late relapse. CHIP status could be a key variable to guide TFR decision-making and monitoring.

No abstract available

No abstract available

Clonal hematopoiesis (CH) is characterized by the acquisition of defined somatic mutations in hematopoietic stem cells (HSC). It is well known that CH contributes to the development of hematological malignancies but also increases the risk of developing non-malignant conditions such as cardiovascular, pulmonary, and inflammatory liver disease. However, less is known about the association between clonal hematopoiesis and solid cancer. Reports suggest that patients with solid cancer have a higher incidence of clonal hematopoiesis at an earlier age and an inferior prognosis. To investigate whether the presence of solid cancer itself can drive the development of clonal hematopoiesis, we analyzed 392 paired tumor and blood samples from patients with advanced cancer. In our cohort, all patients had evidence of clonal hematopoiesis based on a variant allele frequency (VAF) of at least 2%. With respect to a defined set of the 20 most frequently CH-associated genes, we discovered an increased CH rate of 23% of all patients (90 cases, median age of 61 years, defined by a VAF from 2% to 30%). The frequency of mutated genes differed greatly from published data from the general population and cancer patients, with the most common mutations being PABPC1 (39%), KMT2C (28%), RUNX1 (18%), and DNMT3A (10%). In addition, we observed a strong correlation between certain mutations in tumor samples and the frequency of CH. The mutational signature of CH was not mainly associated with a typical chemotherapy-dependent mutational signature, but with an impaired DNA repair capacity. For further investigation, we performed additional experiments in mice, which showed that the presence of malignant cells impairs DNA repair capacity in HSC through inflammatory changes in the stroma. In summary, we were able to show that patients with advanced or recurrent solid tumors have a significantly increased frequency of CH, which is not only the result of prior chemotherapy exposure but the result of diminished DNA repair capacity. This suggests a possible role of solid cancer in promoting the development of CH independent from chemotherapy exposure, which is supported by our additional murine experiments.

Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1–6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.

Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease (CVD). Clonal events in the hematopoietic system resulting from somatic mutations in “driver” genes such as Tet2 are prevalent in elderly individuals in the absence of overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (ARCH), and it is a newly recognized risk factor for CVD. It is unknown whether ARCH and hypertension in the elderly are causally related and, if so, what are the mechanistic features. Objective: Given that the aging process increases the prevalence of hypertension and ARCH, the current experimental study was designed to test the effect of ARCH in hypertension incidence. Methods and Results: A murine model of adoptive bone marrow transplantation to nonconditioned mice was employed to examine the interplay between ARCH and hypertension. Mice carrying Tet2-deficiency in hematopoietic cells resulted in elevated systolic (SBP) and diastolic blood pressure (DBP) as early as one day after challenge with a sub-pressure dose of angiotensin II (Ang II) 200ng/kg/min; SBP (day 1 Tet2 -/- : 148 mmHg± 4 vs. WT: 129±2 mmHg, P=0.002); day 9 Tet2 -/- 159±7 mmHg vs. WT: 139±5 mmHg, P<0.05), and DBP (day 1, Tet2 -/- : 108 ±3 mmHg vs. WT: 100±1 mmHg, P<0.005; day 9, Tet2 -/- : 111 ±4 mmHg vs. WT 107±3 mmHg). The ARCH Tet2 model of CH led to greater macrophage infiltration in the kidney, aorta and mesentery after Ang II compared with WT-treated mice. The Tet2-/- CH condition led to renal NLRP3 inflammasome activation and elevated renal levels of IL (interleukin)-1β (Tet2 -/- 1.4 vs. WT: 0.96, P<0.005) and IL-18 (Tet2 -/- 1.56 vs. WT: 1.18, P<0.005) after Ang II administration. Interestingly, administration of the inflammasome inhibitor MCC950 reversed hypertension seen in the mouse model of Tet2 -/- CH. Conclusion: Our data show that a sub-pressor dose of Ang II promotes hypertension due to elevated renal immune cell infiltration in a Tet2-CH model, promoting IL1-β and IL-18. These data suggest that Tet2 -/- CH carriers could be at elevated risk for the development of hypertension, and that NLRP3 inhibitors could be useful for treating hypertension in this population.

No abstract available

Aging is one of the major negative factors of normal hematopoiesis, characterized by a decline in the self-renewal capabilities of hematopoietic stem and progenitor cells (HSPCs), alongside a myeloid lineage bias, thereby sabotaging the immune system and increasing the risk of malignant transformation. Epigenetic deregulation is a hallmark feature representative of aging and significantly contributes to age-related dysfunction in multiple systems. DNA methylation drifting is commonly observed during aging, especially within the partially methylated domains (PMDs). PMDs are intriguing heterochromatin regions featured by their late-replicating, lamina-associated, and B-compartment localized properties in HiC analysis. While heterochromatin is generally considered devoid of genes, it nonetheless plays a pivotal role in maintaining genomic stability. However, the link between age-related DNA methylation loss in PMDs and heterochromatin dysfunction remains elusive. In this study, we juxtapose the influence of aging on both wild-type (WT) and Tet2 knockout (KO) HSPCs. Tet2 depletion was found to counteract the functional deterioration typically associated with aging by preserving robust self-renewal and repopulation capacities in aging HSPCs. This resistance to functional decay may account for the age-related clonal hematopoiesis observed in Tet2KO HSPCs. At a molecular level, we identified distinct epigenetic regulatory mechanisms mediated by Dnmt3a and Tet2 at heterochromatin. These mechanisms are associated with alterations in 3D genome architecture during HSPC aging. Age-related dysregulation of heterochromatin leads to the upregulation of endogenous retroviruses (ERVs), which subsequently activate intracellular innate immune response and contribute to the functional decline of aging HSPCs. The application of reverse transcriptase inhibitors was shown to suppress ERV production and interferon-stimulated genes (ISGs) expression, thereby ameliorating age-related defects in aged HSPCs. Our findings provide compelling evidence supporting the intricate interplay between DNMT and TET in regulating DNA (de)methylation equilibrium in heterochromatin and euchromatin during stem cell aging. Moreover, our study offers critical insights into the mechanisms underlying age-related heterochromatin dysfunction, which contributes to the functional deterioration of HSPCs during aging.

Background: Age-related clonal hematopoiesis (ARCH) is a precursor state to blood cancers and is associated with epigenetic age acceleration (EpiAgeAccel). While ARCH is associated with increased all-cause mortality and cardiovascular disease, not much is known about these risks with therapy-related clonal hematopoiesis (t-CH) – CH occurring in the context of prior cytotoxic chemotherapy/radiation exposure. Methods: Patients were prospectively recruited for CH and EpiAge assessment from Mayo Clinic between 2022 and 2024. CH status was determined using error corrected sequencing on peripheral blood (PB) DNA (sensitivity 0.5% VAF). Patients with CH were classified as t-CH if they had received chemotherapy or radiation prior to CH detection. All other CH cases were classifed as ARCH. For EpiAge analysis, PB DNA was analyzed using the Illumina MethylationEPIC array. The resulting beta values were used to obtain epigentic age estimates using Horvath’s clock, Hannum’s Clock, PhenoAge, DunedinPACE, and estimated telomere lengths (DNAmTL). Results: 106 (62%) of 170 patients assessed were found to have CH. CH patients were classified into ARCH-63 (59%) and t-CH-43 (41%). While the median chronological age (69 vs 67 years) was similar between ARCH and t-CH, t-CH patients had lower Hgb [10.9g/dL vs. 13g/dL (p=0.0001)], lower platelet [146x109/L vs. 192x109/L (p=0.0132)] and lower WBC [4.4x109/L vs. 5.2x109/L (p=0.0345)]. The 3 most common ARCH mutations were TET2 (20%), DNMT3A (19%), and ASXL1 (14%), while PPM1D (27%), TET2 (18%), and DNMT3A (14%) were most frequent in t-CH. There was no significant difference in median EpiAge via Horvath (68 vs 67.5years p=0.2826), Hannum (65 vs 66 years p=0.9333), or PhenoAge (55 vs 56 years p=0.618) between ARCH and t-CH. However, DunedinPACE of aging was higher in t-CH (1.27 vs 1.18 bioyear/chronoyear p=0.0148) and median DNAmTL was shorter in t-CH (6.35 vs 6.49kb p=0.0247), compared to ARCH (Note patients with telomere biology disorders were excluded). Multivariable regression analysis adjusting for chronologic age, smoking status, and male sex showed that both ARCH and t-CH had EpiAgeAccel via Horvath(5.8years p=0.0001, 3.4 years p=0.051), Hannum(5years p=0.001, 4.5 years p=0.007), and PhenoAge (6.7years p=0.002, 7.6 years p=0.002) clocks. t-CH more than doubled DunedinPACE (0.2 bioyear/chronoyear, p<0.001) of aging compared to ARCH (0.08 bioyear/chronoyear, p=0.026). t-CH also demonstrated a significant decrease in DNAmTL (0.34kb, p<0.001) in comparison to ARCH (0.17kb, p=0.015). With a median follow-up of 20 months, t-CH was associated with worse overall survival in comparison to ARCH, and non-CH patients (p=0.013, 93% vs. 90% alive at 10 months, 87 vs. 72% alive at 20 months). Conclusion: Our prospective CH cohort study validates the association between CH and EpiAgeAccel using several different methylation clocks and for the first time highlights an increased pace of aging and shorter DNAmTL in the context of inferior survival outcomes in t-CH. Citation Format: Marissa Li, Jenna Fernandez, Kristina Kirschner, Tamir Chandra, Kristen McCullough, Sarah Aug, Terra Lasho, Christy Finke, James Foran, Cecilia Arana Yi, Yael Kusne, Talha Badar, Abhishek Mangaonkar, Naseema Gangat, Rachel Simon, Alejandro Ferrer, Mrinal Patnaik. A prospective cohort study of biological aging and epigenetic age acceleration in 106 patients with age and therapy-related clonal hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A015.

Clonal hematopoiesis (CH) serves as a molecular connection between aging and pathological conditions, particularly cardiovascular diseases and hematologic malignancies. Recent progress in genetic sequencing have identified somatic mutations in genes such as TET2, DNMT3A, and JAK2 that drive clonal expansion of hematopoietic stem cells, leading to various systemic effects. These mutations, often termed clonal hematopoiesis of indeterminate potential (CHIP), occur in approximately 10-20% of individuals over 70 years old and significantly impact cardiovascular health through enhanced inflammation and atherosclerosis. Additionally, CHIP mutations serve as precursors to hematologic malignancies, with annual progression rates of 1-2% to conditions such as acute myeloid leukemia and myelodysplastic syndromes. Large cohort studies and animal models have demonstrated that specific mutations in epigenetic regulators and signaling molecules contribute to both cardiovascular pathology and malignant transformation. The relationship between aging, CHIP mutations, and disease progression presents opportunities for novel therapeutic techniques, including targeted anti-inflammatory strategies and epigenetic modulators. These findings have significant implications for risk stratification and early intervention in aging populations, potentially revolutionizing preventive medicine approaches for age-related diseases. Integration of CH screening into clinical practice may enable personalized risk assessment and guide therapeutic decisions, though challenges remain in standardizing detection methods and determining optimal intervention techniques

6517 Background: Clonal hematopoiesis (CH), an age-related condition involving somatic mutations in blood stem cells, increases the risk of myelodysplastic syndrome (MDS), blood cancers and cardiovascular disease through inflammatory pathways. Age-related macular degeneration (AMD), the leading cause of blindness in the developed world, is also characterized by chronic inflammation. An increased prevalence of AMD has been observed in older adults with MDS, but the association between CH and AMD remains unexplored. Understanding this relationship could reveal shared inflammatory mechanisms in age-related diseases and guide prevention strategies. Methods: This retrospective cohort study used exome sequencing and electronic medical records (EMRs) from 467,200 adults ≥40 years of age in the UK Biobank (UKB), recruited between 2006–2010 and followed until 2020. Participants with prevalent blood cancer, AMD, or with missing AMD diagnosis dates were excluded. CH was defined as pathogenic somatic mutations with a variant allele fraction (VAF) ≥0.02. Incident AMD was identified using ICD-10 codes (H35.3). Kaplan-Meier estimates and log-rank tests assessed cumulative incidence, while Cox regression models calculated hazard ratios (HRs), adjusted for age, sex, smoking and hypertension. A separate cohort of 4,079 patients from Dana-Farber Cancer Institute (DFCI) validated findings and enabled granular clinical data abstraction from EMRs. Results: CH was detected in 29,550 (6.8%) individuals of the UKB. The 12-year cumulative incidence (C.I.) of AMD was higher in individuals with CH (n=671, C.I. 2.45%) compared to those without (n=6,728, 1.61%; p<2x10-16). In unadjusted Cox models, individuals with CH had a 51% higher risk of AMD compared to those without (HR =1.51 (95% CI: 1.39–1.63; p < 2×10⁻¹⁶), remaining significant after adjusting for covariates (p=0.023). CH genotypes most associated with AMD risk included ASXL1 (HR: 1.32; p = 0.0146) and splicing factors (HR: 1.54; p = 0.0345). Individuals with CH and AMD had a 33% higher risk of progressing to blindness compared to those without CH, though this was not statistically significant (p = 0.242). In the DFCI cohort (n= 4,079), CH was present in 1,028 (25.2%) individuals. 86 (8.37%) individuals with CH had AMD diagnoses compared to those without CH (n= 86, 3.21%; p = 2.53×10⁻¹⁰), with exudative AMD, a more severe subtype, being more prevalent in CH patients (n=11; p = 1.1×10⁻⁵). Conclusions: There is a significant association between CH and AMD, suggesting that AMD prevalent in individuals with MDS is related to presence of CH in the pre-MDS state. Real world data support these findings, highlighting a trend towards severe AMD subtypes in individuals with CH. The identification of specific genes linked to AMD incidence suggests that certain CH genotypes may confer a higher risk for AMD, highlighting the role of AMD screening in individuals with myeloid malignancy precursor conditions.

Environmental exposures are linked to precancerous hematologic conditions, but studies in cohorts with well-defined exposures are limited. We sequenced blood samples from a large cohort of first-responders exposed to the aerosolized dust and carcinogens from the 9/11 World Trade Center (WTC) disaster and observed a significantly higher prevalence of clonal hematopoiesis (CH) mutations when compared to two sets of control cohorts after controlling for age, race, and sex. Younger exposed first-responders exhibited unconventional CH mutations, with defective DNA repair signatures. Leukemia risk was elevated (3.7% vs. 0.6%, OR=5.73) in WTC-exposed responders with CH versus without CH. Exposure to particulate matter collected from WTC site impaired healthy stem cell while expanding Tet2-mutant CH clones in mice. Inflammation sensor, IL1RAP, was overexpressed in murine CH, and genetic knockdown inhibited mutant clone growth in-vivo. This study links discrete environmental exposure to hematopoietic mutations and leukemia, identifying IL1RAP as a novel therapeutic target in CH.

Hematopoietic stem cells (HSCs) regenerate blood and immune cells throughout life but their function declines with age. Aging HSCs exhibit reduced self-renewal, decreased regenerative capacity, and myeloid-biased differentiation that contribute to increased incidence of immune dysfunction, clonal hematopoiesis and leukemia in older adults. Mitigating age-related declines in HSC function could thus have a profound impact on extending healthspan. Efforts to enhance aged HSC function, however, have had limited success underscoring our incomplete understanding of the underlying causes of age-related stem cell dysfunction. Loss of protein homeostasis (proteostasis) is a hallmark of aging, but whether it contributes to age-related HSC dysfunction is largely unknown. RNA-sequencing studies revealed that many of the top upregulated gene sets in old HSCs are related to proteostasis, suggesting that proteostasis may be challenged in aging stem cells. In surprising contrast, however, we found that old HSCs did not exhibit substantial changes in protein synthesis or accumulate misfolded or unfolded proteins. Given that proteostasis has emerged as fundamentally important for HSC self-renewal, these opposing results raised the possibility that age-related transcriptional rewiring of HSCs may be driven by a selective pressure to preserve proteostasis. Indeed, we determined that aging HSCs activate Hsf1, a key proteostasis sensor and master transcription factor of the heat shock response, whose activation was associated with elevated expression of multiple heat shock proteins in old HSCs. Conditional deletion of Hsf1 had minimal effects on young HSCs but resulted in significant accumulation of misfolded and unfolded protein and decreased self-renewal activity in old HSCs in vivo. These data indicate that HSCs activate Hsf1 to preserve proteostasis and fitness during aging. Although Hsf1 activation helps preserve HSC function during aging, Hsf1 is also activated in many cancers, including acute myeloid leukemia (AML), where it confers stress resistance and disease progression. Hsf1 activation has always been proposed to occur after transformation, but whether pre-existing Hsf1 activation promotes cancer initiation is unknown. We tested if age-related Hsf1 activation in HSCs promoted the emergence of clonal hematopoiesis and leukemia in older adults. We developed a novel model of age-related clonal hematopoiesis by introducing Dnmt3aR878H mutations in rare (~1%) young adult HSCs that enabled us to track clonal expansion throughout life. Dnmt3aR878H HSCs expanded by ~20-fold and dominated the HSC pool by 17 months of age. Remarkably, conditional deletion of Hsf1 severely attenuated the age-related clonal expansion of Dnmt3aR878H HSCs by 81%. These data indicate that age-related Hsf1 activation promotes the emergence of clonal hematopoiesis. Furthermore, we introduced a secondary transforming NrasG12D mutation in Dnmt3aR878H HSCs that led to splenomegaly, an aberrant expansion of pre-leukemic multipotent progenitors, and ultimately a fatal age-associated myeloid neoplasm. Strikingly, preventing age-related Hsf1 activation via conditional genetic deletion significantly extended overall survival and decreased penetrance of fatal neoplasms from 69% to 27% after 1 year. These studies reveal that a selective pressure to preserve proteostasis results in transcriptional reprogramming of aging HSCs that helps preserve stem cell fitness at the cost of increasing the risk of clonal hematopoiesis and cancer. These new connections between molecular proteostasis and physiological changes in aging HSCs could uncover new therapeutic opportunities to prevent clonal hematopoiesis and leukemia by targeting underlying age-related changes in stem cell proteostasis.

Deep sequencing of 2,860 long-term survivors of pediatric cancer identified accelerated clonal hematopoiesis (CH) and characterized STAT3 as a CH gene specific to Hodgkin lymphoma survivors.

Background and Significance: Besides chemotherapy and inherited or acquired bone marrow failure, aging is one of the most important risk factors for the development of clonal hematopoiesis (CH), and both intrinsic and chronological factors may play a role. While initially asymptomatic and referred as to clonal hematopoiesis of indeterminate potential (CHIP), CH frequently leads to adverse clinical consequences with increased risk of cardiovascular disease, certain pulmonary disorders, and other diseases. CHIP carriers experience increased risk of progression to myeloid neoplasia (MN). The process of clonal expansion may be protracted, and its penetrance is difficult to assess due to competing mortalities. While various genetic lesions have been described as common to CHIP, loss of function TET2 mutation (TET2MT) is very common. The prevalence of TET2MT CH increases with age; for instance, our earlier research demonstrates that most cases of myelodysplastic syndrome in patients over age 70 are likely from TET2MT CHIP. TET2MT are prototypic CH lesions, being both weakly leukemogenic in the context of healthy, young hematopoiesis and increasingly strong initiators of leukemogenic cascades in aging populations. In the current study, we investigate whether the progression of CH is not only linked to cell intrinsic properties of TET2MT clones, but also to other extrinsic age-related changes in bone marrow niche, including inflammation, loss of hematopoietic stem cell (HSC) fitness, and quantitative contraction of the HSC compartment. These factors are particularly important for TET2MT CHIP because they may, perhaps in addition to TET2 deficient clones, be subjects of therapeutic or preventive interventions. Methods and Results: We developed novel murine models of Tet2 mutant (Tet2+/- and Tet2-/-) inB6CD45.2, B6TomatoRedmTmG and CD45.1 JaxBoy, and utilized young (8-16 weeks) and old (>16 months) WT mice to dissect the role of cell intrinsic and extrinsic aging factors in CHIP evolution. We utilized various surface markers along with cell intrinsic fluorophores to monitor different hematopoietic compartments. Data analyses were performed in FlowJo™ and statistical analyses were performed using Dunnett's test (sample size n<8) or one-way ANOVA for multiple comparisons. Our models enabled precise monitoring of CH using phenotypic markers. We performed an in vivo marrow competitive bone marrow repopulation assay, where grafts from either young or old WT donors from CD45.2 mice (90%) competed with Tet2-/- B6TomatoRedmTmG (10%) in congenic CD45.1 JaxBoy recipient mice irradiated with 9.2 gray ionizing radiation. The Tet2-/- fractions traced by tdTomato fluorescence and the WT donor fraction traced as tdTomato negative and CD45.2 positive were monitored until sacrifice at 52 weeks. 5 months post-transplant, we observed that the expansion rate of Tet2-/- clone was accelerated (>2-fold, n=5, p =0.006, t-test) when the competitor graft was from old donors compared to young donors. Marrow cells derived from young donors restricted the expansion of Tet2-/- HSC due to better fitness, reducing the proportion of Tet2-/- cells from 80.47% in the transplants from old WT donors to 33.80% in those from young donors (n=5, p=0.0002, t-test) 52 weeks post-transplant at the end of the experiment. In a further analysis, we observed that aging effects on hematopoiesis varied across compartments, notably contracting the T-cell compartment from 49.25% (young WT donors) to 25.08% (old WT donors) (n=5, p=0.0339) consistent with immune cell deficit with aging. Using these models, we have identified that aging HSCs feature a lack of fitness that may contribute to the emergence and expansion of CH. Our data suggest that the age-associated attrition of normal HSCs allows the expansion of TET2MT CHIP. Therefore, enhancing the fitness of a polyclonal, normal HSC compartment by targeting the factors that created such attrition, may restrict or delay clonal evolution and prevent associated morbidities.

Environmental exposures have been postulated to affect the pathogenesis of many human diseases including blood cancers and predisposition conditions such as clonal hematopoiesis (CH). There are few systematic studies that have determined the magnitude of CH in well-defined cohorts of environmental exposures. We conducted deep sequencing analysis of 988 World Trade Center (WTC) responders (firefighters and emergency medical service) exposed to high levels of aerosolized dust, gases, and potential carcinogens associated with the World Trade Center (WTC) disaster to determine the prevalence of CH and the association between CH and leukemia. First, the CH prevalence among WTC-exposed responders was compared to that of two comparison cohorts: non-WTC-exposed firefighters (n=255) and non-WTC-exposed controls (n=195; individuals from the general population). We observed a significantly higher prevalence of CH among WTC-exposed responders (14%) versus non-WTC-exposed firefighters (7%, odds ratio (OR)=3.38; 95% CI 1.90-6.34) and non-WTC-exposed controls (general population; 7%, OR=3.57; 95% CI 1.94-7.01) after controlling for age, race, and sex. Interestingly, we did not observe an increased CH burden among non-WTC-exposed firefighters compared to controls from the general population, contrary to the anticipated increase due to occupational exposure to toxic smoke. Even though DNMT3A and TET2 were the two most common mutated genes, the subsequent spectrum of mutations was distinct in younger WTC-exposed responders (age < 60) and included APC (6.6%), KMT2D(4.8%), ATM (4.8%), PIK3CA (4.2%) CREBBP (3.0%), BRCA2 (2.4%), ERBB4 (2.4%), and ARID1A (2.4%). Additionally, the risk of developing leukemia was elevated (3.7% vs 0.6%; OR, 5.73; 95% CI, 1.24-26.21) in WTC-exposed responders with CH compared to those without CH. Moreover, CH in younger responders was characterized by a higher variant allele frequency (Median VAF of 28% vs 13%) with 70% of the mutations being missense mutations. Analysis of overall mutational signatures in WTC-exposed responders demonstrated an enrichment of aging-related (Signature 1A) and defective homologous-recombination-based repair or BRCA1/BRCA2 mutation-associated signatures in younger WTC-exposed responders. We also observed increased levels of neutrophils, monocytes, and red cell width (RDW) in WTC-exposed responders with CH compared to those without CH, suggestive of elevated inflammation. We created an in vivo model mimicking an 8-hour responder work-shift at the WTC site for responders by administering a single dose of WTC-particulate matter (WTC-PM; chemically characterized matter obtained from Ground Zero) to mice via oropharyngeal instillation. We found that administration of WTC-PM led to impaired hematopoietic stem cell (HSC) function in vivo. We utilized a non-conditioned Tet2+/- bone marrow transplantation-based model of CH and found that WTC-PM exposure accelerated the growth of the mutant clones and increased the expression of IL-1 receptor accessory protein (IL1RAP), a sensor and mediator of inflammatory signals, on Tet2+/- hematopoietic stem-progenitor cells (HSPCs). Heterozygous deletion of Il1rap significantly decreased the expansion of Tet2-mediated CH clones after WTC-PM exposure in vivo. Strikingly, the previously reported resistance to inflammation-mediated toxicity exhibited by Tet2-mutant cells was lost in Il1rap deficient Tet2-mutant cells. Our study demonstrates a novel spectrum of CH mutations in younger, environmentally exposed responders. It shows an increased risk of developing leukemia, increased inflammation, and identifies IL1RAP as a mediator of CH progression and a potential therapeutic target in this context. Our study reveals associations between environmental exposures, hematopoietic stem cell clonal dynamics and somatic blood mutations using a unique cohort with well annotated exposure and clinical histories.

Mosaic loss of the Y-chromosome (LOY) in peripheral blood leukocytes is the most common somatic alteration in men and linked to wide range of malignant and nonmalignant conditions. LOY is associated with age, smoking, and constitutional genetics. Here, we aimed to assess the relationships between LOY, serum biomarkers, and clonal hematopoiesis (CH). LOY in U.K. Biobank was strongly associated with levels of sex hormone binding globulin (SHBG), a key regulator of testosterone bioavailability. Mendelian randomization suggested a causal effect of SHBG on LOY but there was no evidence for an effect of LOY on SHBG. In contrast, age-related CH defined by somatic driver mutations was not associated with SHBG but was associated with LOY at clonal fractions above 30%. TET2, TP53, and CBL mutations were enriched in LOY cases, but JAK2 V617F was depleted. Our findings thus identify independent relationships between LOY, sex hormone levels, and CH.

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Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as “clonal hematopoiesis of indeterminate potential” (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to somatic mutations in hematopoietic cells with a minimum allele fraction ≥ 2% without hematological disease. CHIP depends on age and increases the risk of coronary artery disease (CAD). In their 70s women’s prevalence of cardiovascular disease catches up to that of men. In Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) neutralizing interleukin-1β (IL-1β) in chronic CAD, subjects with TET2 CHIP showed greater reduction of cardiovascular events. However, this substudy did not investigate sex. Hypothesis: We hypothesized that sex modifies the association between CHIP mutations and risk of CAD, and the effects of IL-1β inhibition in CHIP-related atherosclerosis in mice. Methods: Sex differences on the association of CAD and CHIP mutations were investigated using 2 cohorts: the UK and Mass General Brigham Biobanks. CHIP genes showing sex differences in human data were deleted in hematopoietic cells of female and male atherosclerosis-susceptible Ldlr -/- mice. Mice consumed a 0.2% cholesterol high-fat diet with or without an anti-mouse IL-1β monoclonal antibody for 9 weeks. We assessed atherosclerosis by histology and performed mechanistic studies using single-cell RNA sequencing (scRNAseq) of atherosclerotic aortic arch and in vitro bone-marrow derived macrophages. Results: Women with TET2 CHIP had larger hazard ratio for CAD than men in both biobanks. Overall CHIP and other mutations did not demonstrate sex differences in the association with CAD. In Ldlr -/- mice deficient for Tet2 in hematopoietic cells, IL-1β inhibition reduced atherosclerosis in female but not male mice. ScRNAseq revealed more inflammatory cells and more expression of inflammatory genes in hematopoietic Tet2 -/- females than in males. IL-1β inhibition limited these sex differences. In vitro experiments demonstrated that Tet2 deficiency prevents the interaction between estrogen-receptor alpha and histone H3 controlling epigenetic regulation in mouse macrophages. Conclusions: Females with TET2 CHIP have accentuated CAD risk and IL-1β blockade limits Tet2 -augmented atherosclerosis in female but not male mice. These results highlight the importance of study of sex as a biological variable, uncover a new mechanism of Tet2 CHIP on acceleration of atherosclerosis, and inform the design of trials refining allocation of anti-inflammatory therapies in TET2 CHIP.

We analyzed DNA from polymorphonuclear (PMN) cells, monocytes, B cells, and T cells of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Three lineage categories were defined: myeloid (PMN with or without monocytes), myelolympho-B (myeloid and B cells), and multipotent (myeloid, B and T cells). Six individuals with aberrant patterns were excluded from analysis. Ninety-four had a single mutation (56 in DNMT3A, 24 in TET2, 7 in other genes [JAK2, ASXL1, CBL or TP53]). Fourteen had multiple mutations. The lineage restriction patterns of single DNMT3A- or TET2-mutated individuals were different. The proportion of myeloid restricted mutations was higher for TET2 (54.2%, 13 of 24) than for DNMT3A (23.2%, 13 of 56) (P < .05). It was similar for myelolympho-B category but with a 1.5 fold greater proportion of myeloid cells for TET2 individuals (P < .05). Importantly, 0% (0 of 24) of the individuals with TET2 mutation in the multipotent category in contrast to 35.7% (20 of 56) for DNMT3A (P < .01). The clone size predicted multipotent pattern for DNMT3A suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations.

Calcific aortic valve disease (CAVD) is a progressive fibrocalcific pathology of the aortic valve resulting in aortic stenosis (AS), the most common valvular heart disease. Clonal hematopoiesis of indeterminate potential (CHIP) is a condition characterized by the proliferation of blood cell clones with select advantageous somatic mutations. CHIP is an independent risk factor for all-cause mortality and atherosclerotic cardiovascular disease. However, whether CHIP is a risk factor for the development of CAVD is currently unknown. To evaluate whether CHIP is an independent risk factor for CAVD. We tested the association between CHIP and CAVD using data from the UK Biobank (UKB) and the Atherosclerosis Risk in Communities (ARIC) Study. Key exposures were the presence of any CHIP (defined as a variant allele fraction [VAF] ≥2%), large CHIP (VAF ≥10%), and individual CHIP driver mutations (e.g., DNMT3A, TET2, ASXL1, and JAK2) at baseline in the UKB and at visit 5 in ARIC, ascertained using whole exome sequencing (WES). Incident AS was determined in the UK Biobank using a previously validated claims-based definition. Aortic valve hemodynamics (mean gradient and peak velocity) ascertained by echocardiography at ARIC visit 7 were examined as log-transformed continuous measures. Cox models were fitted to test the association of CHIP with incident AS in the UKB. Linear regression was used to test the association of CHIP with aortic valve hemodynamics in ARIC. All models were adjusted for age at sequencing, sex, race, type 2 diabetes, body mass index, smoking, and chronic kidney disease. Among 454,327 individuals with WES in the UKB (mean age 57 years, 46% male sex), 3,444 (0.8%) individuals developed incident AS. Any CHIP was identified in 15,426 (3.4%) individuals. The most common CHIP clones were DNMT3A (9,570 [2.1%] individuals), TET2 (2,211 [0.5%] individuals), and ASXL1 (1,710 [0.4%] individuals). Among 1,963 individuals with WES and visit 7 echocardiographic data in ARIC (mean age 74 years, 42% male sex), any CHIP was identified in 430 (21.9%) individuals. The most common CHIP clones were DNMT3A (226 [11.5%] individuals), TET2 (80 [4.1%] individuals), and ASXL1 (24 [1.2%] individuals). In adjusted analysis in the UKB, large CHIP, TET2 CHIP, ASXL1 CHIP, and JAK2 CHIP were each associated with incident AS (large CHIP: HR 1.22 [95% CI 1.02-1.45], P=0.03; ASXL1: HR 1.52 [1.10-2.02], P=0.02; TET2: HR 1.41 [1.03-1.95], P=0.03; JAK2: HR 3.39 [1.61-7.11], P=0.002). Associations were robust after further adjustment for CAD. In fully adjusted analyses in ARIC, ASXL1, but not other CHIP subtypes, was associated with increased aortic valve mean gradient (P=0.03) and peak velocity (P=0.04). ASXL1 CHIP was associated with incident AS in the UKB and higher aortic valve gradients in ARIC. These data suggest that ASXL1 CHIP is an independent risk factor for the development of CAVD.

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging aging-related risk factor for cardiovascular disease (CVD). However, previous studies suggest that CHIP's relevance to CVD may diminish with advancing age. OBJECTIVES This study aimed to test the association of CHIP and its key subtypes with incident CVD in an older population. METHODS Participants in the Women's Health Initiative Long Life Study completed study assessments in 2012-2013 and underwent high-coverage sequencing (median depth 4,580×). The co-primary exposures were composite CHIP and TET2 CHIP. DNMT3A, ASXL1, JAK2, and non-DNMT3A CHIP were examined as secondary exposures. The primary outcome was incident coronary heart disease. Secondary outcomes were incident heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), ischemic stroke, venous thromboembolism, and cardiovascular death. Multivariable-adjusted Cox models tested associations between CHIP and incident CVD. RESULTS Among 6,677 women (median age 80 years; median follow-up 10.1 years), 2,176 (32.6%) had any CHIP. TET2 CHIP was independently associated with incident coronary heart disease (aHR: 1.36 [95% CI: 1.05-1.77]; P = 0.02), whereas composite CHIP was not (aHR: 1.07 [95% CI: 0.89-1.28]; P = 0.49). Secondarily, TET2 CHIP was associated with HFpEF (aHR: 1.40 [95% CI: 1.03-1.90]; P = 0.03), ASXL1 CHIP with HFrEF (aHR: 3.16 [95% CI: 1.53-6.55]; P= 0.002), and JAK2 CHIP with ischemic stroke (aHR: 2.49 [95% CI: 1.17-5.30]; P = 0.02), venous thromboembolism (aHR: 2.71 [95% CI: 1.11-6.65]; P = 0.03), and cardiovascular death (aHR: 2.62 [95% CI: 1.68-4.11]; P < 0.001). No other significant associations were observed for composite or DNMT3A CHIP. CONCLUSION In an older female cohort, key CHIP subtypes (TET2, ASXL1, and JAK2) were associated with incident CVD, with associations that appeared to differ by CVD outcome. These findings suggest that CHIP remains associated with cardiovascular health into later life. (Women's Health Initiative [WHI]; NCT00000611).

INTRODUCTIONThe mechanism by which CHIP arises and skews hematopoietic differentiation toward specific blood cell lineages remains poorly understood. Limited studies have shown preferential expansion of CHIP clones within myeloid lineages and low lymphoid representation, yet data in cancer populations remain scarce. We aimed to characterize the baseline lineage distribution of CHIP mutations across major peripheral blood (PB) subpopulations using targeted sequencing and droplet digital PCR (ddPCR). METHODSThis descriptive and observational study included patients (pts) with a first cancer diagnosis at age ≥ 60 years and treatment-naïve. PB samples were collected at diagnosis and analyzed using a customized 13-gene NGS panel (DNMT3A, TET2, ASXL1, JAK2, PPM1D, TP53, SF3B1, GNB1, SRSF2, CHEK2, CBL, GNAS, and NRAS) to identify CHIP carriers and their variants.These variants were subsequently tracked in sorted PB granulocytes (GR), monocytes (MO), T-, B-, and NK-lymphocytes isolated by cell shorting. DNA from each fraction was analyzed by ddPCR to quantify fractional abundance (FA) across hematopoietic lineages. Cases with an extracted DNA yield <0.05 µg and/or insufficient read counts for reliable ddPCR analysis were excluded.To characterize the contribution of each subpopulation to the CHIP clone, we compared the absolute FA within each subpopulation and its normalized allelic burden, defined as the ratio of FA in the subpopulation to that in whole blood. RESULTSThe prevalence of CHIP in our cohort of 113 pts is 36% with a median number of variants of 1 (IQR 1-2). With a total of 62 variants, mutations in DNMT3A, TET2, and PPM1D were the most prevalent, accounting for 75% of all variants (36%, 26%, and 13%, respectively), followed by ASXL1 and TP53 (8% each).Variant allele frequency by NGS and FA by ddPCR showed near-perfect correlation (Spearman 0.99), indicating highly comparable measurements. FA differed significantly among PB cell types (p < 0.001), with MO showing the highest clonal burden (median FA 5.8%), followed by GR and NK cells (median FA 3.7% and 2.7%, respectively). Markedly lower levels were observed in B and, particularly, in T cells (median FA 1.4 and 0.3%, respectively; p < 0.001). Paired comparisons confirmed a myeloid predominance (both GR and MO) over B- and T, but not over NK lymphocytes, which also displayed higher FA compared to T cells (p<0.001).Gene-specific analyses uncovered striking differences in lineage involvement. DNMT3A exhibited the strongest T-cell involvement across all genes, with a median normalized clonal burden of 0.28 (IQR 0.12–0.57) compared with its wildtype counterpart (0.03, IQR 0.01–0.14) (p < 0.001). TET2 mutations displayed a broad clonal expansion with higher normalized allelic load in GR (1.36 vs. 1.13, p = 0.04), MO (1.86 vs. 1.25, p = 0.01), B (0.87 vs. 0.47, p = 0.03), and NK cells (1.66 vs. 0.67, p = 0.002), but not among T cells. Conversely, ASXL1 mutations were myeloid-restricted, showing markedly lower normalized FA in B (0.01 vs. 0.65, p = 0.01) and T cells (0.00 vs. 0.11, p = 0.05). TP53 and PPM1D mutations showed no lineage-specific differences. These lineage-specific differences were not influenced by patient age.Analysis by type of neoplasm revealed that pts with B-lymphoproliferative disorders displayed a markedly lower mutational burden in B-cell compartment compared to other lineages (median FA 0, IQR 0-2 vs. 2, IQR 1-9; p=0.02), which correlated with a higher myeloid bias compared to other tumors (median 2.42 vs. 0.97, p=0.04). In contrast, pts with solid tumours including breast, ovarian, various types of gastrointestinal neoplasms, and head and neck cancer, showed no differences in the mutational burden of subpopulations. CONCLUSIONSIn our cohort of cancer patients, CHIP preferentially expanded within the myeloid lineage, with partial involvement of NK cells, and minimal representation in B and T lymphocytes. Gene-specific analyses revealed distinct lineage tropisms: TET2 mutations were broadly distributed across most hematopoietic compartments except T-cells, while DNMT3A displayed the highest relative representation in T lymphocytes, and ASXL1 was largely restricted to myeloid lineages.These findings underscore mutation-specific patterns of hematopoietic involvement, supporting the biological heterogeneity of CHIP and its potential role in modulating clinical phenotype and disease trajectory.

e15017 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have become a critical part of treatment for multiple solid tumors, especially among patients with germline homologous recombination deficiency (HRD). With their significant impact on survival has come a concern for therapy-related myeloid neoplasms (tMN). DNA damage response (DDR) mutations causing clonal hematopoiesis (CH) are the driving force behind the tMNs. We hypothesized that platinum and PARPi therapy have significant variation in their impact on CH, further altered by the presence of HRD. Methods: Serial blood samples from 250 patients with a variety of cancers, primarily prostate, ovarian, and lung cancer treated with PARPi (n = 100) or carboplatin (n = 150) were compared to 176 age-matched patients who were not treated for cancer. Samples were sequenced at an average depth of 19,964x using a sequencing assay that captured the exonic regions of nine common CH genes ( DNMT3A, TET2, ASXL1, TP53, CHEK2 , JAK2, SRSF2, SF3B1, PPM1D ). Mixed bone marrow chimeric mice were created by competitive transplant of Trp53 R172H/+ cells—the murine equivalent of the R175H TP53 hotspot mutation seen in myeloid neoplasms— against wild-type cells. Mice were treated with vehicle (n = 19), cisplatin (n = 16), olaparib (n = 9), or talazoparib (n = 14) for 4 weeks before sequential bleeding and bone marrow collection. Results: The average length of carboplatin treatment was 5.6 months (range 1.15-40.8 months) and 8.76 months (range 1.78-44.4 months) for PARPi treatment. Among patients treated with either carboplatin or PARPi, 51% had on average two DDR CH mutations (range 0-19) versus 23% of untreated patients. Carboplatin induced significantly greater growth of DDR CH compared to PARPi (p = 2.6e-2). Expansion of DDR CH mutations during treatment was significantly reduced in patients with a germline HRD pathogenic variant (N = 44) as compared to those without (N = 276, p < 0.001). No significant expansion of DDR CH mutations was observed after either PARPi (p = 3.9e-2) or carboplatin exposure (p = 1.4e-2) in patients with a germline HRD pathogenic variant. Similarly, within our murine model we observed that cisplatin (p = 5.5e-11) and to a lesser extent talazoparib (p = 0.15) increased Trp53-mutant blood leukocytes. However, the competitive advantage of Trp53-mutant cells during treatment with both cisplatin and talazoparib was lost among mice with hematopoietic-specific Brca1 heterozygote mutations. Conclusions: We observed a high frequency of DDR CH expansion after carboplatin and to a lesser extent PARPi treatment. This expansion was largely abrogated in patients with germline HRD. We validated these findings in a mouse model of Trp53-mutated CH. Our findings suggest that the increased risk of tMN following PARPi is likely influenced by prior exposure to other oncologic therapies, including platinum therapy, and may be modified by HRD status.

Introduction Clonal hematopoiesis (CH) is enriched in patients with cancer and has been linked to adverse outcomes. Although often identified in routine diagnostic testing, prospective data remain limited. To guide risk stratification and therapeutic decisions, our institution launched a multidisciplinary tumor board (CH-MTB) in 2022 to review cases of clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). Methods Patients with a history of cancer and incidental CH detection were referred from either (1) plasma cell-free DNA (cfDNA) sequencing using the FoundationOne Liquid CDx assay (NCT04932525) covering CH-related genes (ASXL1, DNMT3A, IDH1, IDH2, JAK2, MPL, MYD88, SF3B1, TET2, and U2AF1), performed for cancer management. Patients with a somatic mutation in one of these genes and variant allele frequency (VAF) ≥ 10%, or any VAF for JAK2, MPL, or MYD88, were assigned to the cfDNA cohort (all had solid tumors); or (2) presence of unexplained clonal cytopenia assessed by a 174-gene peripheral blood (PB) next-generation sequencing (NGS) panel. These patients were assigned to the PB-NGS cohort (62% solid tumors, 38% lymphoma or multiple myeloma). The Clonal Hematopoiesis Risk Score (CHRS) was calculated for mutations with VAF ≥ 2%; mutations with VAF < 2% were classified as micro-CHIP. ResultsFrom June 2022 to June 2024, 591 patients were prospectively enrolled: 374 in the cfDNA cohort and 217 in the PB-NGS cohort. Median age was 69 years; 52% were female. A history of ≥ 2 primary cancers was reported in 25%. Lung cancer (25%) and non-Hodgkin lymphoma (NHL) (32%) were the most common in the cfDNA and PB-NGS cohorts, respectively. Median treatment lines were 2 (range: 0-12). Compared to the cfDNA group, the PB-NGS patients showed higher rates of thrombocytopenia (39% vs. 6%, p < 0.01), neutropenia (15% vs. 2%, p < 0.01), anemia (59% vs. 36%, p < 0.01), macrocytosis (21% vs. 8%, p < 0.01), and elevated red cell distribution width (RDW) (34% vs. 17%, p = 0.03). Top mutations in the PB-NGS cohort included DNMT3A (47%), PPM1D (27%), TET2 (26%), TP53 (22%), and ASXL1 (12%). In the cfDNA cohort, DNMT3A (61%), TET2 (33%), ASXL1 (25%), JAK2 (25%), and MYD88 (6%) mutations predominated. Based on the CHRS, patients were low-risk (25% vs. 35%), intermediate-risk (36% vs. 22%), and high-risk (12% vs. 1%) in the PB-NGS vs. cfDNA cohorts (p < 0.001). Micro-CHIP was observed in 18% and 17%, respectively. Concordance between cfDNA and PB-NGS was assessed in 67 patients (11%) with both tests (84% collected within 1 year). Of the 132 mutations covered by both panels, 74 (56%) were detected by both, 51 (39%) only in cfDNA, and 7 (5%) only in PB-NGS. Most cfDNA-only mutations (82%) had a VAF < 2%. For mutations with VAF ≥ 2%, VAFs correlated strongly between cfDNA and PB-NGS (r = 0.77), specifically for DNMT3A (r = 0.92) and TET2 (r = 0.69). After a median follow-up of 18 months (range: 0-35), 20 new hematologic malignancies were diagnosed: 7 at first CH-MTB visit (myelodysplastic syndrome [MDS]: 2; myeloproliferative neoplasm [MPN]: 2; chronic myelomonocytic leukemia [CMML]: 1; chronic myeloid leukemia: 1; NHL: 1) and 13 during follow-up (MDS: 9; MPN: 1; MDS/MPN: 2; NHL: 1). Among the 12 with MDS or CMML, 8 had clonal evolution, 4 acquired new mutations, and 4 had TP53 alterations. Of those progressing to MDS, 64% had a high or very high IPSS-M score. Univariable analysis adjusted for cohort affiliation showed that patients with ≥ 2 treatment lines (hazard ratio [HR] = 1.8), presence of CCUS (HR = 1.8), elevated RDW (HR = 2.3), and CHRS high-risk (HR = 3.5) were at risk for shorter overall survival (OS) (p < 0.01). In multivariable analysis of CHRS components adjusted for cohort affiliation, presence of CCUS (HR = 1.7) and elevated RDW (HR = 2.1) independently predicted shorter OS (p ≤ 0.01). Competing risk analysis showed that CHRS high-risk group (HR = 11, p = 0.03), presence of ≥ 2 CHIP mutations (HR = 9.3, p < 0.01), and VAF ≥ 20% (HR = 5.7, p < 0.01) were associated with progression to hematologic malignancies. Conclusion Our MTB dedicated to CH proved the importance of early detection of hematologic malignancies in patients with cancer. CHRS high-risk group, high VAF, and multiple CHIP mutations were associated with progression to hematologic malignancies. These findings highlight the need for oncology-specific CH risk models to identify patients warranting early CHIP interception.

Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging aging-related risk factor for cardiovascular disease (CVD). However, previous studies suggest that CHIP’s relevance to CVD may diminish with advancing age. To test the association of CHIP (subtypes) with coronary heart disease (CHD) and other common CVD outcomes in an elderly population. Participants in the Women’s Health Initiative (WHI) Long Life Study (LLS) completed study assessments approximately 15 years after enrollment in the main WHI study. Individuals with prevalent hematologic malignancy were excluded. CHIP status was ascertained using single-molecule molecular inversion probe sequencing (median coverage depth 4,609x) of peripheral blood DNA. Given the heterogeneity of CVD associations among major CHIP drivers and stronger associations previously observed for TET2 CHIP, the co-primary exposures were (1) composite CHIP and (2) TET2 CHIP, with CHIP defined as a variant allele fraction of ≥2%. DNMT3A, non-DNTM3A, ASXL1, and JAK2 CHIP were examined as secondary exposures. Individuals without CHIP constituted the reference group. The primary outcome was incident CHD. Secondary outcomes were incident heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF), ischemic stroke, and cardiovascular death. Outcomes were ascertained using standardized physician review, classification, and adjudication. Cox models tested associations between CHIP and CVD with follow-up starting at the LLS visit, adjusting for age, race, body mass index, diabetes, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, cholesterol-lowering and antihypertensive medication use, and smoking status. Our analytic cohort included 6,572 women (median [interquartile range] age 80 [73-85] years, 2,123 [32.3%] with any CHIP at the LLS visit) followed up for a median of 10.2 (7.1-10.8) years. TET2 CHIP was independently associated with incident CHD (HR, 1.39 [95% CI, 1.07-1.81]; P=0.015). In secondary analyses, TET2 CHIP was also associated with HFpEF (HR, 1.50 [95% CI, 1.07-2.12]; P=0.02), ASXL1 CHIP with HFrEF (HR, 3.81 [95% CI, 1.74-8.33]; P<0.001), and JAK2 CHIP with ischemic stroke (HR, 2.68 [95% CI, 1.26-5.71]; P=0.01) and cardiovascular death (HR, 2.69 [95% CI, 1.70-4.26]; P<0.001). No significant associations were observed with composite or DNMT3A CHIP (Table 1). Findings were consistent in sensitivity analyses incorporating non-cardiovascular death as a competing risk and, for secondary outcomes, in analyses further adjusted for prevalent CHD. In this cohort of elderly women, key subtypes of CHIP (TET2, ASXL1, and JAK2) were independently associated with incident CVD, with evidence of heterogeneous associations across CHIP driver mutations. These findings validate previous observations in younger cohorts and suggest that CHIP continues to be associated with cardiovascular health well into later life.Associations between CHIP and CVD

Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis of indeterminate potential (CHIP) is frequent in aging and involves the expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, the risk factors that contribute to CHIP-associated clonal hematopoiesis (CH) are poorly understood. Obesity induces a proinflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data for 47,466 individuals with validated CHIP in the UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in the waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1, and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and that a proinflammatory state could potentiate the progression of CHIP to more significant hematologic neoplasia. The calcium channel blockers nifedipine and SKF-96365, either alone or in combination with metformin, MCC950, or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP-mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in individuals with obesity.

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BACKGROUND The expansion of hematopoietic stem cells caused by acquired somatic mutations (clonal hematopoiesis [CH]) is a novel cardiovascular risk factor. The prognostic value of CH in patients with carotid atherosclerosis remains to be evaluated. OBJECTIVES This study assessed the prognostic significance of CH in patients with atherosclerosis as detected by ultrasound of the carotid artery. METHODS We applied deep sequencing of selected genomic regions within the genes DNMT3A, TET2, ASXL1, and JAK2 to screen for CH in 968 prospectively collected patients with asymptomatic carotid atherosclerosis evaluated by duplex sonography. RESULTS We detected clonal markers at variant allele frequency ≥2% in 133 (13.7%) of 968 patients (median age 69.2 years), with increasing prevalence at advanced age. Multivariate analyses including age and established cardiovascular risk factors revealed overall presence of CH to be significantly associated with increased risk of cardiovascular death (HR: 1.50; 95% CI: 1.12-2.00; P = 0.007), reflected also at the single gene level. The effect of CH was more pronounced in older patients and independent of the patients' inflammatory status as measured by high-sensitivity C-reactive protein. Simultaneous assessment of CH and degree of carotid stenosis revealed combined effects on cardiovascular mortality, depicted by a superior risk for patients with >50% stenosis and concomitant CH (adjusted HR: 1.60; 95% CI: 1.08-2.38; P = 0.020). CONCLUSIONS CH status in combination with the extent of carotid atherosclerosis jointly predict long-term mortality. Determination of CH can provide additional prognostic information in patients with asymptomatic carotid atherosclerosis.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD-protective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.

OBJECTIVE Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI = 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI = 1.05, 2.08) and ASXL1 (HR 1.76; CI = 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI = 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

BACKGROUND Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES This study sought to evaluate whether CHIP is associated with incident HF. METHODS CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

Clonal hematopoiesis of intermediate potential (CHIP), the outgrowth of mutant hematopoietic stem cell (HSC) clones without blood count abnormalities, increases the risk of hematological malignancies and cardiovascular disease. The most common CHIP driver mutations are in TET2, DNMT3A, TP53, ASXL1, and JAK2, which are also classically seen in myeloid malignancies. Asxl1 is the CHIP variant most strongly associated with smoking. In a UK Biobank study of >30,000 participants, 69% of people with ASXL1 mutations were past or current smokers, while TET2 and DNMT3A mutations also had a significant but more modest association with smoking status. However, few studies have investigated the impact of the popular cigarette alternative, the electronic cigarette (e-cig). As the popular alternative to smoking, one of the biggest CHIP risk factors, it is crucial to characterize the impact of e-cigarettes on systemic inflammation and hematopoietic function. This study aims to elucidate the mechanisms by which CHIP mutations regulate hematopoiesis and inflammation in response to e-cigarette exposure and antioxidant modulation. N-acetylcysteine (NAC) is a safe and freely available dietary supplement that has anti-inflammatory and antioxidant properties. To test the impact of cigarettes vs. E-cigarettes on in vivo ASXL1 expansion, lethally irradiated CD45.1/2 recipient mice were transplanted with equal numbers of whole bone marrow cells from wild type (WT) (CD45.1) and ASXL1-/- mice (CD45.2). Eight weeks post-transplant, mice were exposed to smoke (n=12) or room air (n=8) using a nose-only inhalation exposure system for 2 hours/day, 4 days/week. Smoke-exposed mice were exposed to traditional cigarette smoke for 3 months, then this cohort was split in two, with one half switching to air (i.e. smoking “cessation”) or to e-cigarette aerosol (smoking “substitution”). At regular intervals, peripheral blood was drawn to determine the percentage of WT and ASXL1 cells by flow cytometry. In all groups, the percentage of Asxl1-/- in peripheral blood initially fell from ~60% to 40% and was stable throughout the exposure period. CBCs were mostly normal, with a slight derangement of platelets and monocytes near the end of exposure. At euthanasia, liver and spleen weights were normal in all mice. We measured TNFa production in LPS-stimulated splenocytes via ELISA and found no significant difference at 24hours. However, when plated in methylcellulose, splenocytes from both the smoke-air “cessation” and smoke-e-cigarette “substitution” cohort had a 30% decrease in colony proliferation. Peritoneal macrophages displayed similar rates of phagocytosis of fluorescent Zymosan S. cerevisiae particles. This was unexpected, as literature suggests smoke exposure should impair macrophage phagocytosis. Further studies will include use a smaller number of particles to better differentiate limited phagocytosis. In a secondary transplant, transplanted cells from the smoke-e-cigarette “substitution” cohort had reduced engraftment and survival. Together, these results suggest that traditional cigarette smoke and e-cigarette aerosols can both alter hematopoietic stem cell function but potentially by distinct cellular processes. To explore the mechanisms of e-cigarette inflammation, whole BM from WT or CHIP-mutant mice or peripheral blood mononuclear cells (PBMCs) from MPN patients were incubated overnight with cigarette smoke extract (CSE), e-cigarette aerosol+/-nicotine, and/or NAC and plated in methylcellulose for colony formation assays. In WT and Tet2+/- cells, CSE and e-cigarette liquid significantly reduces colony formation at similar rates. However, the Tet2-/- cells were more resistant to e-cigarette reduction of colony formation. In WT cells, NAC rescued CSE-reduced colony formation, but not e-cigarette-reduced colony formation. This suggests that the effects of CSE are related to reactive oxygen species that may be mitigated an antioxidant, while the e-cigarette extract is reducing colony formation by a different mechanism unaffected by NAC. Taken together, we can conclude that the impact of e-cigarettes on hematopoietic stem cell function is complex and warrants further characterization to improve safety for the millions of users. The inflammatory nature of smoking provides a context to study the impact of this environment on CHIP-mutant competition.

Clonal hematopoiesis (CH) is the increase in somatic clones carrying mutations in hematopoietic stem cells. This biological condition can lead to cancer and is implicated in the development of atherosclerosis and cardiovascular diseases. CH of indeterminate potential (CHIP) refers to somatic mutations in genes that are associated with the development of Coronary heart disease (CHD) and leukemia.  Now, with next-generation sequencing, we can detect mutations even if they are present in only a small number of cells in the tissue sample being studied. Consequently, numerous studies have shown that mutations in the DNMT3A, TET2, ASXL1, and JAK2 genes found in the blood are associated with coronary heart disease. The purpose of our study is to detect a genetic variant of genes in Kazakh patients with atherosclerosis, which will further allow us to study the role of CHIP in increasing the risk of developing coronary microvascular dysfunction and CHD. We perform high-throughput whole-exome sequencing in patients with atherosclerosis. The object of the study is samples delivered from the clinic “National Scientific Cardiac Surgery Center” in Astana. The study is carried out in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Genomic DNA extraction was performed on 245 samples using the Illustra Blood Kit (Cytiva, USA). Qualitative and quantitative assessment of the extracted genomic DNA was conducted using the NanoDrop 2000 (Thermo Scientific) and Qubit 2.0 (Thermo Fisher Scientific). Subsequently, DNA library preparation was carried out using the Illumina DNA Prep with Exome 2.5 Enrichment kit. Quality control of the resulting DNA libraries was conducted on a 2100 Bioanalyzer system using the Agilent DNA 1000 Kit and High Sensitivity DNA kit (Agilent Technologies). Following assessment of the DNA library concentration on Qubit 2.0, they were loaded onto the high-performance sequencer NovaSeq 6000 (Illumina, USA) following the manufacturer’s protocol. We conducted human whole-exome sequencing on 245 samples to identify somatic clones in the peripheral blood of patients with atherosclerosis. Patients were divided into three groups – low risk, middle, and high risk of atherosclerotic complications. Bioinformatic analysis of sequence data were performed. We created list of genes associated with CH to deep analysis and to interpreter the data in patient groups. Subsequently, DNA extraction from the remaining samples is performed, followed by sequencing on the NovaSeq 6000 platform. Analysis of the resulting sequenced data is currently underway. Further research and monitoring of CHIP will enable us to understand the mechanisms underlying the development of cardiovascular diseases and to devise a comprehensive management plan for patients with this pathology. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and  Nazarbayev University CRP (211123CRP1608).

Introduction: Although the inferred “fitness” of clonal hematopoesis (CH) driver mutations differs depending on the gene mutation, the impact of environmental factors that may promote or impair CH expansion remain largely unknown. We hypothesized that obesity influences the clonal expansion rate of common CH driver mutations. Methods: To test this hypothesis, we first interrogated data from the UKBiobank (UKBB) (n=425,573 exomes) to evaluate the relationship between body mass index (BMI) (kg/m2) and four common CH mutations, namely DNMT3A, TET2, ASXL1, and JAK2. For functional studies we focused on JAK2V617F, using a novel Fgd5-CreER-Jak2V617F mouse model we generated. In this model, Jak2V617F expression is induced in a small percentage of long-term (LT)-HSC which are tracked sequentially in primary mice in an unirradiated bone marrow niche. To quantify Jak2V617F expression in the model, we developed a digital droplet PCR assay. We also generated a chimeric bone marrow transplant Jak2V617F model and performed bulk RNA-sequencing (RNAseq) on purified lineagelow Sca-1+ c-kithigh (LSK) cells expressing Jak2V617F or wild-type Jak2, isolated from the same mouse. Finally, we performed single-cell RNAseq on Jak2V617F-expressing c-kithigh cells purified from chimeric transplant mice. Mice fed an obesity diet received 60 kcal% fat while mice fed a control diet received 10 kcal% fat. Results: In UKBB analyses, we identified genotype-specific patterns of association between BMI and the presence of CH mutations. JAK2 (OR 0.51; 95% CI 0.27-0.96; p=0.036) and DNMT3A mutations (OR 0.92; 95% CI 0.87-0.97; p=0.0028) were negatively associated with a BMI >30 relative to BMI <25, whereas mutations in ASXL1(OR 1.40; 95% CI 1.23-1.60; p=8.8x10-7) and TET2 (OR 1.16; 95% CI 1.04-1.31; p=0.0095) were positively associated with BMI >30. To further explore the negative association between JAK2V617F and obesity, we generated a cohort of Fgd5-CreER-Jak2V617F mice and fed half the mice an obesity diet and the other half a control diet. After 24 weeks, Jak2-mutant mice fed the control diet developed a significantly higher hematocrit (HCT) as compared to Jak2-mutant mice fed the obesity diet (p=0.0043). The HCT remained significantly higher in control mice as compared to obese mice over a 46-week period (p<0.0001). Strikingly at 46 weeks, 5/7 mice (71%) fed the control diet showed signs of MPN as compared with 0/6 mice (0%) fed the obesity diet. Furthermore, overall survival was significantly improved in Jak2-mutant obese mice as compared to Jak2-mutant mice fed a control diet (p=0.03). Subsequently, after the death of most control mice, one Jak2-mutant obese mouse developed an elevated HCT, indicating that obesity prolonged the latency to MPN development in Jak2V617F mice. In the chimeric transplant model, gene set enrichment analysis (GSEA) showed significantly increased interferon alpha (NES=2.55, FDR≈0), interferon gamma (NES=2.26, FDR≈0), and interleukin-6 (NES=2.15, FDR=5.46x10-05) signaling in Jak2-mutant LSK cells isolated from obese animals as compared to wild-type LSK cells, a finding not observed in control mice. Single-cell RNAseq experiments further validated these findings, where we identified interferon induced transmembrane protein 1 (IFITM1) as one of the most differentially upregulated genes in Jak2-mutant LT-HSCs from obese mice (adjusted p-value=1.08x10-54) as compared to wild-type LT-HSCs, and unlike Jak2-mutant LT-HSCs from control mice. Conclusions: To our knowledge, our study is the largest to date to evaluate the relationship between obesity and CH and the first to investigate the negative association between JAK2V617F CH and obesity, using functional studies. We developed a novel Fgd5-CreER-Jak2V617F mouse model, which allowed us to study the transition from CH to overt MPN in an unperturbed, non-irradiated bone marrow niche. Transcriptomic profiling points to activation of the interferon signaling pathway in Jak2-mutant HSC as a possible mechanism by which JAK2-mutant LT-HSC may preferentially exhaust during obesity. These findings support testing pegylated interferon as a potential treatment for individuals with JAK2-mutant CH and a clinical protocol is currently under development at our institution. Ongoing functional studies are investigating additional metabolic targets in LT-HSC with the goal of uncovering novel treatment approaches for JAK2-mutant CH.

Clonal hematopoiesis (CH)-associated mutations increase the risk of atherosclerotic cardiovascular diseases. However, it is unclear whether the mutations detected in circulating blood cells can also be detected in tissues associated with atherosclerosis, where they could affect physiology locally. To address this, the presence of CH mutations in peripheral blood, atherosclerotic lesions and associated tissues was assessed in a pilot study of 31 consecutive patients with peripheral vascular disease (PAD) who underwent open surgical procedures. Next-generation sequencing was used to screen the most commonly mutated loci (DNMT3A, TET2, ASXL1 and JAK2). Twenty CH mutations were detected in peripheral blood of 14 (45%) patients, 5 of whom had more than one mutation. TET2 (11 mutations, 55%) and DNMT3A (8 mutations, 40%) were the most frequently affected genes. Altogether, 88% of the mutations detectable in peripheral blood were also present in the atherosclerotic lesions. Twelve patients also had mutations in perivascular fat or subcutaneous tissue. The presence of CH mutations in PAD-associated tissues as well as in blood suggests that CH mutations may make a previously unknown contribution to PAD disease biology.

10522 Background: The contribution of germline genetics on the emergence of CHIP in patients with solid tumor malignancies is not well understood. We hypothesized that those with germline (g) alterations in homologous recombination repair genes (gHRR) and BRCA-associated cancers (breast, ovarian, prostate, pancreas) would have different rates of CHIP than those without. Methods: We analyzed a large real-world Tempus multimodal database of paired germline and somatic DNA sequencing results. CHIP was calculated based on the presence of pathogenic or likely pathogenic alterations in any one of 16 CHIP-associated genes ( ASXL1, BCOR, BCORL1, CBL, CREBBP, CUX1, DNMT3A, GNB1, JAK2, PPM1D, PRPF8, SETDB1, SF3B1, SRSF2, TET2, U2AF1) with a variant allele frequency of at least 2%. Patients with g alterations in BRCA1, BRCA2, ATM, CHEK2, and PALB2 were compared to those without gHRR alterations (sporadic). Results: In breast cancer, patients with g BRCA1 (n = 104) mutations were younger (med 43 yrs) at diagnosis compared to sporadic cases (n = 6,546 med 56yrs) but had similar rates of CHIP (3% vs 5%). Those with gPALB2 (n = 42 med age 55) had the highest rate of CHIP (14%). gBRCA2 (n = 148; med age 52), gATM (n = 57 med age 52), and gCHEK2 (n = 57 med age 53) and similar rates of CHIP (3%, 4%, 7%). In ovarian cancer, patients with gBRCA1 (n = 137 med age 53) were younger at diagnosis than sporadic cases (n = 3,979 med age 63) with similar rates of CHIP (4% vs 3%). Those with gBRCA2 (n = 83 med age 61) were similar (4%) and gPALB2 (n = 11 med age 68) had the highest rate of 9%. CHIP was not detected among patients with g ATM (n = 23 med age 61) or g CHEK2 mutations (n = 9, med age 59). In prostate cancer, 4% of patients with sporadic cases had CHIP (n = 4,183 med age 66) compared to 4% in gBRCA2 (n = 109 med age 63) and 5% in gATM (n = 44 med age 66). gCHEK2 had 17% prevalence of CHIP (n = 12 med age 66) followed by gPALB2 (n = 12 med age 69). There were no CHIP mutations found among those with g BRCA1 (n = 16 med age 64). In pancreatic cancer, patients with g BRCA2 (n = 89 med age 64) and PALB2 (n = 20 med age 62) were younger at diagnosis, compared to sporadic cases (n = 5,176 med age 67) with lower rates of CHIP (1% gBRCA2, 0 PALB2, 5% sporadic). The highest proportion was in gBRCA1 patients (n = 20 med age 63) with 10%, gCHEK2 (n = 16 med age 68) with 6% and gATM (n = 60 med age 66) with 5%. Conclusions: Despite younger age at diagnosis, patients with g BRCA1 had similar or higher rates of CHIP within breast and ovarian cancer. Women with g PALB2 alterations and breast and ovarian cancer, as well as men with g CHEK2 mutations and prostate cancer, had higher rates of CHIP. These data suggest that gHRR mutations may influence the prevalence of CHIP among patients with BRCA-associated cancers and more research is needed.

INTRODUCTION Prevalence of CHIP in cancer patients (pts) is estimated at about 25%, its presence being associated with inferior outcomes and with increased risk of development of therapy-related myeloid neoplasms (TRMN). Despite the increased body of knowledge on cancer and CHIP, processes driving the selection of clones and their latter malignant transformation have not been fully elucidated. We hypothesized that CHIP in cancer pts might not only lead to TRMN but also affect the prognosis of the primary neoplasm and its treatment-related toxicity. Our study aims to describe the prevalence and dynamics of CHIP in treatment-naïve pts with cancer and to analyze its impact on clinical outcomes. METHODS This study included 103 pts with a first cancer diagnosis at age ≥ 60 years and eligible for anticancer treatment without prior exposure to cytostatic agents. Peripheral blood (PB) samples were collected at diagnosis and 6 months after treatment. A customized NGS panel covering common CHIP genes ( DNMT3A, TET2, ASXL1, JAK2, PPM1D, TP53, SF3B1, GNB1, SRSF2, CHEK2, CBL, GNAS, and NRAS) was used to identify CHIP-positive (VAF≥ 1%) and CHIP-negative cases. Clonal dynamics were assessed through NGS at 6 months after treatment, categorized as ‘growing’ when their VAF increased by more than 25% compared to the baseline, ‘shrinking’ when VAF decreased by more than 25% compared to the baseline and ‘stable’ if it remains unaltered. RESULTS Baseline characteristics are shown in table 1.The prevalence of CHIP in our cohort was 35%, with an average of 1.5 somatic variants per patient and 54 identified variants, and a median VAF of 4.7% (IQR 2.5-11.0%). Notably, mutations in DNMT3A (33%), TET2 (28%), and PPM1D (13%) were the most prevailing gene aberrations, accounting for nearly 75% of all variants, while other common CHIP genes such as ASXL1 (9%) or JAK2 (0%) were less frequent. TP53 variants represented 9% of all mutations, whereas SF3B1, GNB1, SRSF2, and CBL each accounted for 2%. Breast cancer pts displayed a significantly higher prevalence of CHIP compared to other primary neoplasms (66% vs. 36%, p=0.01) whereas no patient with bladder neoplasm presented CHIP at diagnosis (p=0.04). These observations were not warranted only by differences in the age or smoking habit of these subgroup of neoplasms. The mutational spectrum of CHIP across different cancer categories was comparable. Among 20 paired samples sequenced (baseline and post-genotoxic exposure), 41% of all variants exhibited a growing pattern, 31% a shrinking pattern, and 28% remained static (Figure 1). Platinum-based therapy exposition promoted clonal expansion in DNMT3A mutations (p=0.03), while this effect was not observed in PPM1D or other genes, likely due to the low sample size. Age, tobacco use, and type of primary neoplasm did not appear to influence clonal fitness. There were no significant differences in the incidence of infectious complications or chemotherapy-induced hematologic toxicity between CHIP-positive and CHIP-negative cohorts. With the current follow-up time (16.8 months), the overall response (ORR) and complete response rates (CR) appeared comparable (ORR: 94% in CHIP-positive vs. 85% in CHIP-negative; CR: 79% vs. 70%, respectively). A patient with diffuse large B-cell lymphoma and CHIP ( ASXL1, PPM1D, and TP53 variants) developed a TRMN (MDS-MD) 7 months after completing R-CHOP treatment. CONCLUSION The prevalence of CHIP in our cancer pts cohort is 35%, with breast cancer cases displaying a CHIP occurrence around 62% not previously reported. Our study highlights an enrichment of mutations in PPM1D in treatment-naïve cancer pts, surpassing the frequency of ASXL1 in contrast to prior literature. Genotoxic therapy promotes clonal expansion in 41% of variants in our cohort; although factors influencing CHIP fitness remain poorly understood, DNMT3A showed heightened susceptibility to platinum therapy. Finally, and in contrast contrast with our initial hypothesis, we found no evidence of impaired outcomes in the CHIP population. These results emphasize the need for further longitudinal follow-up. Acknowledgements: This work was supported by two grants from the Instituto de Salud Carlos III (PI20/00881 and PI 20/00531)(Co-funded by European Regional Development Fund. ERDF, a way to build Europe). 2021 SGR 00560 (GRC) Generalitat de Catalunya; economical support from CERCA Programme.

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5021 Background: Somatic mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion in a process called clonal hematopoiesis (CH). CH increases the risk of developing myeloid neoplasms and shortens overall survival (OS), primarily linked to increased cardiovascular (CV) mortality. The impact of CH in metastatic solid cancers has been conflicting, with shorter OS in a broad cancer cohort but prolonged OS in metastatic colorectal cancer, which may be influenced by prior cytotoxic therapy that can promote emergence of CH. As AR pathway inhibitors (ARPIs) are associated with CV adverse events (AE), exploring the impact of CH in patients (pts) with mCRPC is of interest. Methods: A 9 gene targeted DNA sequencing panel designed to capture common CH mutations ( DNMT3A, TET2, ASXL1, PPM1D, TP53, CHEK2, SRSF2, SF3B1, JAK2) was applied to pre-treatment peripheral blood samples of 957 pts enrolled in the Alliance A031201 phase 3 trial of enzalutamide versus enzalutamide plus abiraterone/prednisone in the first line mCRPC setting. No difference in OS was found between treatment arms. The primary endpoint was the impact of CH on OS; secondary and exploratory endpoints included progression-free survival (PFS) and associations with baseline comorbidities and AEs (hematologic and CV). Cox proportional-hazards and logit models were adjusted for treatment arm, age, and radiation therapy (RT). Results: CH was common with 57% of pts having low CH (VAF>0.5% in 1+ mutation, L-CH), 24% having standard CH (VAF>2%, CH), and 7% having high CH (VAF>10%, H-CH). 4% of pts had 2+ CH mutations and 1% had 3+ mutations. Patients with CH were older (73.1 vs 70.2) and had higher rates of prior RT (58.4% vs 55.7%) and prior chemotherapy (3.9% vs 2.2%). No differences in OS were detected in pts with L-CH, CH, or H-CH. Similarly, no differences in PFS or baseline CV comorbidities were seen in any CH group. Pts with H-CH and TET2-mutated CH had statistically higher odds of any CV event (adjusted p=0.0004 and p=0.010, respectively) There was also a difference in the occurrence of major adverse CV events (MACE) by H-CH status (5.8% vs. 1.9%, adjusted p=0.042), while there was no difference seen for CH (3.4% vs 1.8%, adjusted p=0.147). Regarding hematologic AEs, one pt with a TP53 mutation (VAF 0.94%) developed myelodysplastic syndrome. Conclusions: CH did not affect OS or PFS in pts with mCRPC treated with ARPIs in the A031201 trial. However, CH with VAF>10% and TET2-mutated CH were associated with an increased rate of all CV AEs, suggesting an additive effect of ARPI therapy and CH on adverse CV outcomes. Confirmatory studies are warranted to assess whether CH should be considered in the risk-benefit discussion for pts receiving ARPIs.

499 Background: Clonal hematopoiesis of indeterminate prognosis (CHIP) is recently recognized as a pre-malignant condition and independent cardiovascular risk factor with doubled risk of coronary heart disease, cerebrovascular events, and worsened heart failure outcomes. Despite this recognition, multidisciplinary CHIP clinics are near-uniformly associated with tertiary centers where only a minority of oncology patients receive care. Tennessee Oncology is a large community oncology practice with over 200 providers at 35 sites of care throughout Tennessee and North Georgia. Here, we report the characteristics of two years of patients with common CHIP mutations as we prepare to launch our CHIP clinic. Methods: Patients with solid tumors who underwent either tissue- or blood-based comprehensive genomic profiling from May 2021 to May 2023 were reviewed. Patients with incidental discovery of DNMT3A, ASXL1, TET2, JAK2, IDH1/2, SRSF2, U2AF1, SF3B1, and ZRSR2 mutations are classified as having CHIP. High-risk mutation profile was defined as >1 mutation or a single mutation with variant allele frequency (VAF) of ≥10%. In patients sequenced >1x, only initial sequencing was used. The presence of cardiovascular disease or traditional risk factors was based entries into the patients’ “problem list” or use of medications commonly used to treat these conditions. Results: Over a two-year period, 3599 patients underwent sequencing and CHIP mutations were identified in 1069 (29.7%) patients. The median VAF was 1.58% and 585 patients had at least one mutation with a VAF of ≥2%. Median age at sequencing was 69.6 years. Distribution between males/females was similar. Lung cancer was the most common histology (n=328) followed by breast (n=122) and colon (n=121). DNMT3A mutations (n=829) were most frequently seen followed by TET2 (n=353), ASXL1 (n=335), SRSF2/U2AF1/SF3B1/ZRSR2 (n=147), JAK2 (n=138), and IDH1/2 (n=104). Nearly two-thirds of patients had a high-risk mutational profile with >1 mutation (n=479) or VAF ≥10% (n=185). Assessing traditional risk factors for cardiovascular and cerebrovascular disease, essential hypertension and type 2 diabetes were present in 56.4% (n=603) and 30.1% (n=322) of patients, respectively, and a minority of patients had established coronary disease (n=181) or heart failure (n=74). Twenty-three percent (245/1069) had no cardiovascular risk factors. Conclusions: In a large community practice, 29.7% of patients have common CHIP mutations – most of whom are considered high-risk based on current risk stratification criteria. Many patients also have traditional risk factors or established cardiac disease underscoring the strong association between CHIP and cardiovascular disease. A community-based, multi-disciplinary CHIP clinic would enhance these patients’ care and potentially lead to improved outcomes.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with aging, increased risk of myeloid neoplasms, inflammation-related diseases, and cardiovascular diseases. Mutations occur most commonly in the transcriptional regulator genes DNMT3A, TET2 and ASXL1. Furthermore, JAK2 mutation has been linked with coronary heart disease (CAD). COVID-19 is associated with endothelial hyperinflammation, cardiovascular and thromboembolic events (TE). Excess of mortality in these patients (pts) has been shown to be partly associated to pulmonary embolism (PE) and in situ pulmonary thrombosis.

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Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon associated with increased cardiovascular (CV) risk, independent of traditional risk factors, which can make risk stratification a challenge. The residual cardiovascular risk (RCVR) test is a recently developed 27-protein model that has been shown to predict 4-year risk of a CV event (myocardial infarction, stroke, transient ischemic attack, heart failure hospitalization, death) in independent replication cohorts of at-risk populations. Objectives: The goal of this analysis was to evaluate whether the RCVR test could detect significant differences in CV risk between CHIP+ and CHIP- sub-populations using data from the CANTOS trial (NCT01327846), a study that enrolled subjects with a history of cardiovascular disease that were evaluated for their CHIP status. Methods: RCVR test scores were generated from SomaScan v4.1 assay data on EDTA plasma samples from the CANTOS trial. Baseline analysis compared mean RCVR test scores in CHIP+ (n=174) and CHIP- (n=1794) subjects who were either randomized into the placebo or canakinumab treated arms. A linear model of RCVR distributed by CHIP status, with fixed effects of treatment arm, age, and sex was evaluated in a Type III ANOVA to determine covariate adjusted between group differences in RCVR test scores. Results: The mean predicted RCVR test score was 4.96% greater at baseline for CHIP+ subjects compared to CHIP- subjects after adjusting for covariates (p=2.07e-3). Conclusions: The RCVR test predicted that the absolute risk of a cardiovascular event within four years is significantly greater for CHIP+ individuals. These results suggest RCVR may be able to capture the increased CV risk conferred by novel risk factors like CHIP status and highlight the potential utility of multi-protein-based prognostic test as a tool for CV risk assessment. Further analysis of longitudinal time points from the placebo arm of the trial are planned to assess whether cardiovascular risk increases at a different rate in CHIP+ and CHIP- individuals over time.

Background: Clonal haematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with an increased risk of cardiovascular disease (CVD). Mutations in CHIP-related genes such as DNMT3A, JAK2, and TET2 are common and linked to accelerated atherosclerosis and adverse outcomes. There is a growing body of evidence at a global level. However, data on CHIP in Kazakhstani populations remains limited. Materials and methods: The aim of this study was to evaluate the prevalence and characteristics of 74 genes associated with CHIP among Kazakhstani patients with atherosclerotic disease. A total of 401 patients with pre-existing CVD, divided by risk levels according to ESC/EAS (2019) recommendations was divided: low-risk (n = 74), high-risk (n = 135) and very-high-risk (n = 192). Variant annotation and interpretation were performed using international genomic databases (ClinVar, ExAC, 1000 Genomes) and the ACMG/AMP classification system through InterVar. Results: According to ACMG criteria, we identified 2 pathogenic variants (DNMT3A and PDS5B) and 3 likely pathogenic variants (JAK2 and CEBPRA) variants, and for the uncertain significance counts 701 variants, the CLNSIG classification shows 2 pathogenic variants (MPL) and 1 likely_pathogenic (CREBBP) and pathogenic/likely pathogenic 1 variant (ASXL1). There were 174 female participants (mean age 53.8 ± 9.1 years) and 227 male participants (mean age 52.2 ± 9.9 years). Most patients were ≥50 years across all risk categories. Among females, the very-high-risk group showed a balanced age distribution, while in males it was predominantly younger. Low and high-risk groups were dominated by older patients, especially men, indicating potential sex differences in risk onset. Conclusion: This study provides the first evidence of CHIP-associated variants across 74 genes in Kazakhstani patients with atherosclerotic disease. The study identified pathogenic, likely pathogenic, and numerous variants of uncertain significance, highlighting their potential contribution to increased cardiovascular risk in this population. These findings emphasise the importance of CHIP in identifying cardiovascular risk and the value of genomic screening. Acknowledgements: Supported by the Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP23490249), (AR19677442), (BR24993023), (BR24992841), (BR21881970) and Nazarbayev University CRP (211123CRP1608). Key words: clonal hematopoiesis of indeterminate potential, atherosclerosis, CHIP, mutations, cardiac disorders

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Graphical Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in myocardial infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP. Mosaic loss of the Y chromosome (mLOY), a common marker of clonal hematopoiesis in men, has emerged as a potential candidate for modulating cardiovascular risk associated with CHIP. In this study, we aimed to ascertain the risk linked to each somatic mutation or mLOY and explore whether mLOY could exert an influence on the cardiovascular risk associated with CHIP. Methods: We conducted an examination for the presence of CHIP and mLOY using targeted high-throughput sequencing and digital PCR in a cohort of 446 individuals. Among them, 149 patients from the CHAth study had experienced a first MI at the time of inclusion (MI(+) subjects), while 297 individuals from the Three-City cohort had no history of cardiovascular events (CVE) at the time of inclusion (MI(-) subjects). All subjects underwent thorough cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. Our investigation aimed to determine whether mLOY could modulate inflammation, atherosclerosis burden, and atherothrombotic risk associated with CHIP. Results: CHIP and mLOY were detected with a substantial prevalence (45.1% and 37.7%, respectively), and their occurrence was similar between MI(+) and MI(-) subjects. Notably, nearly 40% of CHIP(+) male subjects also exhibited mLOY. Interestingly, neither CHIP nor mLOY independently resulted in significant increases in plasma hs-CRP levels, atherosclerotic burden, or MI incidence. Moreover, mLOY did not amplify or diminish inflammation, atherosclerosis, or MI incidence among CHIP(+) male subjects. Conversely, in MI(-) male subjects, CHIP heightened the risk of MI over a 5 y period, particularly in those lacking mLOY. Conclusions: Our study highlights the high prevalence of CHIP and mLOY in elderly individuals. Importantly, our results demonstrate that neither CHIP nor mLOY in isolation substantially contributes to inflammation, atherosclerosis, or MI incidence. Furthermore, we find that mLOY does not exert a significant influence on the modulation of inflammation, atherosclerosis burden, or atherothrombotic risk associated with CHIP. However, CHIP may accelerate the occurrence of MI, especially when unaccompanied by mLOY. These findings underscore the complexity of the interplay between CHIP, mLOY, and cardiovascular risk, suggesting that large-scale studies with thousands more patients may be necessary to elucidate subtle correlations. Funding: This study was supported by the Fondation Cœur & Recherche (the Société Française de Cardiologie), the Fédération Française de Cardiologie, ERA-CVD (« CHEMICAL » consortium, JTC 2019) and the Fondation Université de Bordeaux. The laboratory of Hematology of the University Hospital of Bordeaux benefitted of a convention with the Nouvelle Aquitaine Region (2018-1R30113-8473520) for the acquisition of the Nextseq 550Dx sequencer used in this study. Clinical trial number: NCT04581057.

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Importance Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased risk of cardiovascular disease (CVD) events and mortality. However, there are no approved therapies for preventing or treating CHIP. Objective To investigate whether low-dose aspirin might benefit older adults with CHIP for the primary prevention of CVD. Design, Setting, and Participants This was a prespecified substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) double-blind, randomized clinical trial of daily low-dose aspirin vs placebo evaluating disability-free survival, which took place at primary and community care facilities in the US and Australia. Enrollment was from March 2010 to December 2014, and the randomized trial ended in June 2017. Community-dwelling Australian adults aged 70 years and older without a diagnosed cardiovascular event, atrial fibrillation, a serious intercurrent illness likely to cause death within the next 5 years, anemia, or a current or recurrent condition with a high risk of bleeding were included in the original study. Of 19 114 in the original trial, 11 402 were included in the substudy, and 9434 were included in the analysis. Follow-up for this substudy went through June 2022, with data analysis in February 2025. In-trial median (IQR) follow-up time was 4.6 (3.5-5.6) years, and posttrial observational follow-up was 8.7 (7.5-10.1) years from randomization. Interventions Participants were randomized to aspirin, 100 mg, daily or placebo. Main Outcomes and Measures CHIP was measured in blood specimens collected at trial entry. Major adverse cardiovascular events (MACEs), including fatal and nonfatal ischemic stroke, nonfatal myocardial infarction and coronary heart disease death, and clinically significant bleeding were adjudicated by independent expert committees blinded to trial-group assignments. Results A total of 9434 participants (median [IQR] age, 73.7 [71.6-77.1] years; 5067 [54%] female) provided a sample at baseline for analysis, 2124 of whom (23%) had CHIP at variant allele fraction (VAF) ≥2%, with 532 (5.6%) at ≥10% VAF. CHIP was not associated with increased risk of MACEs at 2% to 10% VAF (adjusted hazard ratio [aHR], 0.84, 95% CI, 0.68-1.03; P = .09) or ≥10% VAF (aHR, 0.80, 95% CI, 0.57-1.12; P = .19). However, CHIP was associated with increased risk of clinically significant bleeding (2%-10% VAF: aHR, 1.24; 95% CI 1.02-1.51; P = .03; ≥10% VAF: aHR, 1.21; 95% CI, 0.85-1.73; P = .28). There was no evidence of a differential effect of aspirin according to presence of CHIP on MACEs (without CHIP: HR, 0.91; 95% CI, 0.72-1.16; 2%-10% VAF: HR, 1.40; 95% CI, 0.77-2.53; ≥10% VAF: HR, 1.33; 95% CI, 0.52-3.37; heterogeneity P = .35) or clinically significant bleeding (without CHIP: HR, 1.64; 95% CI, 1.22-2.30; 2%-10% VAF: HR, 1.45; 95% CI, 0.82-2.57; ≥10% VAF: HR, 1.41; 95% CI, 0.49-4.07; heterogeneity P = .91). Conclusion and Relevance In this secondary analysis of a randomized clinical trial of daily low-dose aspirin in healthy adults 70 years and older, CHIP was not associated with higher CVD risk. However, participants with CHIP had a greater risk of clinically significant bleeding. There was no evidence that participants with CHIP were more likely than those without CHIP to benefit or experience more harm from aspirin when used for primary prevention of CVD events. Trial Registration ClinicalTrials.gov Identifier: NCT01038583.

Key Points Question Is the clonal hematopoiesis (CH) risk score associated with all-cause and disease-specific mortality in older adults with CH? Findings In this cohort study that included 3871 individuals without hematologic malignant neoplasms at baseline, 24.2% had CH. Individuals with low-risk CH (59.9% of those with CH) had survival similar to those without CH, and participants with high-risk CH (6.2% of those with CH) had increased all-cause, cardiovascular, and hematologic malignant neoplasm–related mortality. Meaning These findings suggest that the CH risk score is associated with overall and disease-specific mortality in older adults with CH and could be used to identify individuals with CH who need more intensive surveillance.

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Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the clonal expansion of hematopoietic stem cells carrying certain genes associated with an increased risk of hematological malignancies. Our study analyzes the influence of CHIP on the risk of heart disease and cardiovascular events in a population with chronic kidney disease (CKD). A total of 128 patients were prospectively followed up for 18 months to detect major cardiovascular events (MACE). To detect the presence of silent heart disease, troponin I, NT-Pro-BNP, and coronary calcification were measured. A massive sequencing was performed to detect CHIP. A total of 24.2% of the patients presented CHIP, including that which was only pathogenic. The most frequently affected gene was TET2 (21.1%). Using multivariate logistic regression analysis, the presence of CHIP was not related to coronary calcification (OR 0.387, 95% CI 0.142–1.058, p = 0.387), nor was it related to troponin I or NT-Pro-BNP. A total of nine patients developed major cardiovascular events. Patients with CHIP did not have a higher risk of major cardiovascular events, although patients with DNMT3A did have a higher risk (HR 6.637, 95% CI 1.443–30.533, p = 0.015), independent of other variables. We did not find that CHIP was associated with a greater risk of silent heart disease or cardiovascular events, although those affected by DNMT3a, analyzed independently, were associated with a greater number of cardiovascular events.

Supplemental Digital Content is available in the text. Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2. In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. Methods: We analyzed exome sequences from 35 416 individuals in the UK Biobank without prevalent CVD, to identify participants with DNMT3A or TET2 CHIP. We used the IL6R p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by IL6R p.Asp358Ala. Results: We identified 1079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (hazard ratio, 1.27 [95% CI, 1.04–1.56], P=0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21–2.09], P<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29–0.73], P<0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89–1.01], P=0.08; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=0.036). Conclusions: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.

Expanding human presence in space through long-duration exploration missions and commercial space operations warrants improvements in approaches for quantifying crew space radiation health risks. Currently, risk assessment models for radiogenic cancer and cardiovascular disease consider age, sex, and tobacco use, but do not incorporate other modifiable (e.g., body weight, physical activity, diet, environment) and non-modifiable individual risk factors (e.g., genetics, medical history, race/ethnicity, family history) that may greatly influence crew health both in-mission and long-term. For example, clonal hematopoiesis of indeterminate potential (CHIP) is a relatively common age-related condition that is an emerging risk factor for a variety of diseases including cardiovascular disease and cancer. CHIP carrier status may therefore exacerbate health risks associated with space radiation exposure. In the present study, published CHIP hazard ratios were used to modify background hazard rates for coronary heart disease, stroke, and hematologic cancers in the National Aeronautics and Space Administration space radiation risk assessment model. The risk of radiation exposure-induced death for these endpoints was projected for a future Mars exploration mission scenario. Here we show appreciable increases in the lifetime risk of exposure-induced death for hematologic malignancies, coronary heart disease, and stroke, which are observed as a function of age after radiation exposure for male and female crew members that are directly attributable to the elevated health risks for CHIP carriers. We discuss the importance of evaluating individual risk factors such as CHIP as part of a comprehensive space radiation risk assessment strategy aimed at effective risk communication and disease surveillance for astronauts embarking on future exploration missions. Space radiation exposure is a major hazard of spaceflight that may increase cancer and cardiovascular disease risks for future astronauts exploring the moon and Mars. There is a need for accurate risk assessment that considers individual risk factors to support informed consent and medical management of these risks. Clonal hematopoiesis of indeterminate potential (CHIP) is a condition that occurs when copies of variant cells accumulate in the blood of otherwise healthy individuals. CHIP is an emerging risk factor linked with blood cancers and cardiovascular disease. We evaluated how CHIP can alter space radiation health risks in astronauts for a Mars exploration mission scenario. We find large increases in lifetime risk of space radiation exposure-induced death for hematologic malignancies and cardiovascular disease in CHIP carriers. These results suggest that increased screening may help facilitate better management of radiation risks. Werneth et al. evaluate the impact of clonal hematopoiesis of indeterminate potential (CHIP) on health risks associated with space radiation exposures in astronauts. This work highlights the importance of considering personalized risk factors, such as CHIP, for effective risk assessment and monitoring of astronaut health.

Key Points Question Is clonal hematopoiesis of indeterminate potential (CHIP) associated with increased risk of therapy-related cardiovascular disease among patients receiving chemotherapy, radiotherapy, or immunotherapy? Findings In this cohort study of 8004 participants, CHIP was associated with higher risk of heart failure in patients receiving cardiotoxic cancer therapies, with effects more pronounced among those receiving higher cumulative doses of chemotherapy. Meaning CHIP testing may improve cardiovascular risk stratification in oncology patients and support earlier cardio-oncology consultation, monitoring, and risk-based primary prevention strategies for high-risk cancer survivors.

No abstract available

Inactivating mutations of the epigenetic modifier TET2 are frequent in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). These mutations in hematopoietic stem and progenitor cells (HSPCs) impart a clonal advantage with increased self-renewal. CHIP is associated with an increased risk of hematological malignancies and, surprisingly, with atherosclerotic cardiovascular disease, supported by studies in mice and humans. The heightened cardiovascular risk in CHIP patients may result from a pro-inflammatory slant of the mutant HSPC progeny, particularly monocytes and macrophages, independent from the risk imparted by elevated LDL cholesterol levels. Targeting molecules like IL-1β may provide a strategy to lower the risk of cardiovascular morbidity in patients with CHIP. However, as an alternative strategy, administration of drugs that selectively suppress the growth of mutant CHIP clones in the bone marrow (BM) might reduce the risk of both i) progression to MDS or hematologic malignancy and of ii) atherosclerotic cardiovascular disease. This study focused on identifying drugs that reverse the inflammatory and atherosclerotic properties of TET2-mutant macrophages. Our previous investigations demonstrated that the nuclear export inhibitor eltanexor selectively kills Tet2-mutant HSPCs in zebrafish embryos and reduces the number of mutant colonies in murine colony formation assays. A murine competitive repopulation model of CHIP tested the in vivo efficacy of eltanexor. We found that eltanexor selectively reduces Tet2-mutant circulating monocytes while having no effect on overall total white blood cell counts. Moreover, a second trial using Ldlr-/- atherosclerosis-prone mice consuming a high-cholesterol diet, showed that treatment with eltanexor selectively reduces the amount of aortic atherosclerotic plaque formation as well as spleen weight in mice injected with Tet2+/- (mutant) BM cells, whereas eltanexor had no significant effect in mice injected with Tet2+/+ (wild-type) BM cells. Single-cell CITE-seq analysis of Ldlr-/- mice injected with a mix of Tet2+/- and Tet2+/+ BM cells showed that eltanexor selectively reduces the percentage of Tet2+/- HSPCs. Additionally, CITE-seq analysis revealed a significant reduction in pro-inflammatory macrophages in the arterial wall after eltanexor treatment, along with a decrease in IL-1β expression by these cells. As TET2 functions in mechanistically regulating gene regulation through epigenetic DNA methylation, we employed ChIP-seq and CUT&RUN-Seq technologies to investigate the mechanisms underlying enhancer dysregulation caused by loss of Tet2. Enhancer profiling of bone marrow-derived macrophages showed that the negative regulator of the macrophage inflammatory response, ATF3, is associated with a super-enhancer. Notably, the ATF3 super-enhancer emerged as the largest super-enhancer in wild-type macrophages but was reduced in Tet2-mutant macrophages. Our investigation also revealed that ATF3 binds with IL-1β at H3K27ac modified regions, and this binding was significantly diminished in Tet2-mutant macrophages. Remarkably, treatment with eltanexor restored the binding of ATF3 to IL1β, providing a mechanism to explain the anti-inflammatory effect of eltanexor concordant with our in vivo results. In summary, this study proposes eltanexor treatment as a novel therapeutic approach to specifically target TET2-mutant cells in individuals with CHIP and sheds light on the underlying mechanisms of the pro-inflammatory slant of TET2-mutant macrophages. These findings offer potential new avenues for precise therapies in humans with CHIP and associated cardiovascular risks from atherosclerosis.

No abstract available

Importance Despite current standards of cardiovascular care, a considerable residual burden of risk remains in both primary and secondary prevention. Clonal hematopoiesis of indeterminate potential (CHIP) has recently emerged as a common, potent, age-associated, independent risk factor for myocardial infarction, stroke, heart failure events, and survival following percutaneous aortic valve intervention. The presence of CHIP results from the acquisition of somatic mutations in a small number of leukemia driver genes found in bone marrow stem cells, leading to the expansion of leukocytes clones in peripheral blood. The association between CHIP and cardiovascular disease likely involves activation of the inflammasome pathway. More common DNA sequencing identifies individuals with CHIP who then seek advice regarding management of their cardiovascular risk. Observations Using clinical vignettes based on real encounters, we highlight some of the diverse presentations of CHIP, ranging from incidental identification to that detected during cancer care, that have brought patients to the attention of cardiovascular practitioners. We illustrate how we have applied a consensus-based approach to the evaluation and management of cardiovascular risk in specific patients with CHIP. Since we currently lack evidence to guide the management of these individuals, we must rely on expert opinion while awaiting data to furnish a firmer foundation for our recommendations. Conclusions and Relevance These vignettes illustrate that the management of CHIP should involve an individualized plan based on features such as comorbidities, life expectancy, and other traditional cardiovascular risk factors. Because individuals with CHIP will increasingly seek advice from cardiovascular specialists regarding management, these examples provide a template for approaches based on a multidisciplinary perspective. The current need for reliance on expert opinion illustrates a great need for further investigation into the management of this newly recognized contributor to residual cardiovascular risk, both in patients who are apparently well and those with established cardiovascular or malignant disease.

No abstract available

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is common in older adults, but the prognostic significance is unknown. We studied the prevalence of CHIP and its mortality in older adults and investigated whether the CHIP risk score (CHRS) -tool to predict hematologic malignancies (HM)- is associated with mortality in this population. Method: In ARIC cohort, CHIP was identified using exome sequencing, and CHRS scores were calculated using demographic, blood parameters, and molecular features. Individuals with CHIP were categorized into low- (CHRS≤9.5), intermediate- (9.5<CHRS<12.5), and high-risk (CHRS ≥12.5) groups. The primary outcome was all-cause death, and secondary outcomes were death from HM and cardiovascular disease (CVD). Results: In 3871 participants without a history of HM (aged 75.7 ± 5.2 years, 58.5% female, 23.1% Black), we identified 938 (24.2%) with CHIP, of whom 562 (59.9%) were low risk, 318 (33.9%) intermediate risk, and 58 (6.2%) high risk by the CHRS. During a median follow-up of 7.13 years, 570 (19.4%) deaths occurred in participants without CHIP and 128 (22.8%), 93 (29.2%), and 33 (56.9%), in the CHRS groups, respectively. Using multivariable competing risk regression, the hazard ratio HR (95% confidence interval) for all-cause mortality was 1.09 (0.90-1.32, P = 0.35), 1.13 (0.90-1.42, P = 0.29), 2.57 (1.75-3.77, P <0.001), for low-, intermediate-, and high-risk CHIP, respectively. ( Fig. 1A ) Compared to those without CHIP, in the high-risk CHIP, the HR of death from HM (6 deaths of 58, 10.3%) was 25.92 (8.04-83.57, P <0.001) and from CVD (12 of 58, 20.7%) was 2.97 (1.59-5.53, P <0.001). ( Fig. 1B ). Conclusions: CHIP can be identified in one-fourth of older adults, and most were low-risk and had the same survival. However, individuals with high-risk CHIP face not only an elevated risk of death from HM but also a threefold higher risk of death from CVD. The latter was the most common cause of death in this group. Funding: NHLBI, NCI, NPCR

Introduction: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for patients with relapsed or refractory lymphoma, and use of HCT has contributed to a growing number of survivors. Despite these improvements in outcomes, long-term survivors of lymphoma are at high risk of developing clinically significant cardiovascular disease (CVD) which, to date, has largely been attributed to pre-HCT cardiotoxic therapeutic exposures (e.g. anthracyclines, radiation) and modifiable risk factors (e.g. hypertension, diabetes, dyslipidemia) after HCT. In the general population, clonal hematopoiesis of indeterminate potential (CHIP), which refers to clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with aging-related health conditions including CVD. Accumulating data suggests CHIP is more prevalent in cancer patients compared to age-matched controls, due in part to clonal selection after genotoxic stressors. There is a paucity of information about the association between CHIP and CVD after HCT, including its interaction with modifiable risk factors and subsequent impact on survival after HCT. Methods: This was a retrospective cohort study of 861 consecutive patients who underwent autologous HCT for lymphoma between 2010 and 2016, with available pre-HCT DNA obtained from peripheral blood stem cells. We performed targeted exome sequencing of DNA (92 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CHIP (variant allele frequency ≥2%). CVD outcomes of interest included de novo heart failure, coronary artery disease and stroke after HCT. Five-year cumulative incidence of CVD was calculated taking into consideration competing risk of death. Fine-Gray multivariable regression was used to evaluate the association between CHIP and CVD, adjusting for demographic, clinical and therapeutic factors. The Kaplan-Meier method was used to examine the effect of CHIP on overall survival after HCT. Results: Median age at HCT was 55.7 years (range 18.4-78.1 years); 63.3% were male; race/ethnicity: non-Hispanic White (56.9%), Hispanic (26.1%), Asian (10.8%), Black (5.1%); 78.0% had non-Hodgkin lymphoma; comorbidities at HCT: hypertension (32.1%), dyslipidemia (16.4%), diabetes (10.1%), high (≥3) HCT-comorbidity index (CI) score (46.1%). Nearly all patients (94.3%) had received anthracycline-based chemotherapy prior to HCT, and 63.3% were treated with cumulative dose ≥300mg/m 2; 6% had chest radiotherapy. Overall, 186 patients (21.7% of the cohort) had at least one CHIP variant and 57 (6.6%) had ≥2 variants. DNMT3A, PPM1D, TET2 and TP53 were the most frequently mutated genes. In total, 74 patients developed CVD within five years from HCT. The 5-year cumulative incidence of CVD was significantly higher in patients with CHIP (20.9% vs 9.1%, p<0.001), compared to those without CHIP, and there was a graded relationship between number of CHIP variants and incidence of CVD. In the adjusted (age, cancer diagnosis, HCT-CI, modifiable cardiovascular risk factors) multivariable model, CHIP was significantly and independently associated with a nearly two-fold (HR: 1.8, 95% CI=1.1-3.1; P=0.020) risk of CVD, as well as the individual outcome of heart failure (HR: 2.3, 95%CI=1.3-4.3; P=0.008). Patients who had both CHIP and hypertension had a 3-fold (HR: 3.0, 95%CI=1.4-6.5, p=0.006) risk of CVD (reference: no CHIP, no hypertension). Overall 5-year survival after HCT was significantly worse in patients with CHIP, compared to those without CHIP (47.2% vs 68.2%, p<0.001; adjusted HR: 1.9, 95%CI=1.4-2.6), attributed to the higher burden of non-relapse mortality in patients with CHIP. Conclusions: In this well-characterized and demographically diverse cohort of lymphoma patients undergoing HCT, CHIP was highly prevalent and associated with a significantly higher risk of CVD after HCT, with the highest risk among those with CHIP and hypertension. We confirmed the poor overall survival rate in patients with CHIP, independent of patient and disease-related risk factors. These findings highlight the potential role of CHIP as a novel biomarker to better define CVD risk in patients with lymphoma prior to HCT, setting the stage for better screening and implementation of interventions (e.g., aggressive management of modifiable risk factors) to reduce the risk of CVD and to ultimately improve long-term health outcomes after HCT.

No abstract available

Importance Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways. Objective To test whether CHIP is associated with the development of myocarditis and pericarditis. Design, Setting, and Participants This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025. Exposures Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures. Main outcomes and measures The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases. Results Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation. Conclusions and Relevance In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

Clonal hematopoiesis (CH) is a frequently observed phenomenon in aging individuals without apparent illness and exhibits an increased prevalence in cancer patients. Mechanistic studies indicate that mutant immune cells alter the tumor microenvironment, leading to increased inflammation, blood vessel formation, and immune cell exhaustion. Paradoxically, these changes also preserve stem-like T-cell pools that can be utilized by immunotherapy. CH may be incidentally detected in patients whose solid tumors are profiled by next-generation sequencing. Clinically, CH confers higher risks of therapy-related myeloid neoplasms, cardiovascular and inflammatory toxicities, and context-specific changes in treatment efficacy. Moreover, tumorinfiltrating CH independently shortens survival. Two validated risk scores can inform the risk for myeloid malignancy, yet surveillance, cardiometabolic management, and regimen selection still primarily rely on expert consensus. Because CH may be discovered incidentally, rigorous confirmation of variant origin when CH is suspected is essential to avoid misdirected therapy. We propose a pragmatic approach: confirm CH with paired blood sequencing when feasible; integrate high-risk features into risk stratification, counseling, and monitoring for cytopenias and cardiovascular events; and prefer less genotoxic regimens when the oncologic benefit is comparable. Early trials blocking interleukin-1β suggest that targeting inflammation driven by CH may improve outcomes in patients with solid tumors. Prospective studies informed by mutation analysis and tracking clonal changes and inflammatory markers are needed to determine if routine CH assessment can be integrated into precision oncology to improve outcomes for patients with solid tumors and CH.

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a novel risk factor for cardiovascular diseases. CHIP is characterized by the expansion of hematopoietic stem cell clones harboring somatic mutations in genes such as TET2, DNMT3A, and ASXL1, which are implicated in inflammation, atrial remodeling, and hypercoagulability. These mutations foster a pro-inflammatory and pro-thrombotic environment conducive to arrhythmogenesis, thereby linking CHIP to the development and progression of atrial fibrillation (AF). Mechanistic insights indicate that CHIP contributes to atrial fibrosis, disrupts calcium signaling, and exacerbates oxidative stress, all of which heighten susceptibility to AF. Clinical studies, including epidemiological and Mendelian randomization analyses, further support the association between CHIP and an increased risk of both incident and progressive AF, with specific mutations such as TET2 and ASXL1 identified as significant contributors. Additionally, CHIP has been linked to adverse outcomes in AF, including elevated rates of heart failure, thromboembolism, and mortality. Understanding CHIP’s role in AF pathophysiology offers opportunities for the development of precision medicine approaches, providing novel avenues for early intervention and targeted AF treatment. This review synthesizes current mechanistic and clinical evidence on the role of CHIP in AF, emphasizes its potential as a biomarker for risk stratification, and explores emerging therapeutic strategies targeting CHIP-associated pathways.

Vascular contributions to cognitive impairment and dementia (VCID) represent a major public health challenge in the aging population, with age-related cerebromicrovascular dysfunction playing a critical role in its development. Understanding the mechanisms underlying cerebromicrovascular aging is crucial for devising strategies to mitigate this burden. Among the key hallmarks of aging, genomic instability and genetic heterogeneity have emerged as significant drivers of age-related diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a prominent manifestation of this instability, characterized by the non-malignant expansion of hematopoietic stem cell clones that harbor somatic mutations. CHIP is well-established as a contributor to atherosclerosis and cardiovascular disease through its promotion of chronic inflammation. Given that aging is also a major risk factor for cerebral small vessel disease (CSVD) and VCID, it is likely that the same aging processes driving large artery atherosclerosis in CHIP carriers also impair small vessels, including the cerebral microvasculature. While the role of CHIP in large vessel disease is well-documented, its specific contributions to cerebrovascular aging and microvascular dysfunction remain poorly understood. This review explores the potential role of CHIP in age-related cerebrovascular pathologies, with a particular focus on its contribution to CSVD. We discuss how CHIP-related mutations can promote inflammation and oxidative stress, potentially leading to endothelial dysfunction, dysregulation of cerebral blood flow (CBF), blood–brain barrier (BBB) disruption, microvascular inflammation, and cerebral microhemorrhages. Given the potential implications for VCID, elucidating these mechanisms is critical for developing targeted therapies aimed at reducing the burden of cognitive decline in aging populations. This review aims to highlight the current knowledge gaps and encourage further research into the intersection of CHIP, CSVD, and cognitive aging.

Atrial fibrillation (AF) is the most common sustained arrhythmia. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the clonal expansion of hematopoietic stem cells due to acquired mutations without hematologic malignancies, has emerged as a potential risk factor for AF. This narrative review summarizes the shared risk factors between CHIP and AF, including age, lifestyle behaviors and cardiometabolic conditions. It then explores the underlying mechanisms including inflammation, atrial fibrosis and abnormal red cell distribution width. Among these, inflammation is a central driver that promotes abnormal calcium handling, which further accelerates atrial remodeling. For specific mutations, TET2 mutations correlate strongest with AF, with other mutations in genes such as ASXL1, JAK2, TP53, PPM1D and spliceosomes, may also modulate AF susceptibility, though their precise roles require further investigation.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of hematopoietic stem cells harboring leukemogenic mutations in the absence of overt malignancy. Strongly associated with advancing age, CHIP is detected by next-generation sequencing of peripheral blood in more than 20% of individuals over 80, most commonly through mutations in DNMT3A, TET2, ASXL1, and PPM1D. While CHIP confers over a four-fold increased risk of hematologic malignancy, it has recently emerged as a key determinant of cardiometabolic health. Epidemiological data indicated a 40% higher cardiovascular disease (CVD) risk events and a 34% increase in all-cause mortality among CHIP carriers, with specific mutations and larger clone sizes conferring greater cardiovascular burden. Preclinical studies have shown that macrophages deficient in TET2 or DNMT3A drive interleukin (IL)-1β/IL-6 inflammasome activation, thereby promoting atherosclerosis and metabolic dysfunction, whereas the JAK2V617F mutation accelerates thrombosis. CHIP integrates into a broader network of dysregulation encompassing adiposity and inflammaging, which underlies its association with diverse comorbidities, including type 2 diabetes (T2D), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD). Multi-omics approaches have identified epigenetic and proteomic signatures correlated with CHIP expansion, providing potential biomarkers for risk stratification. Despite growing evidence of its systemic impact, CHIP screening remains limited to research settings. Emerging therapeutic strategies, including inflammasome inhibition, STING modulation, and epigenetic restoration, highlight its potential as a modifiable risk factor. This narrative review synthesizes current epidemiological, mechanistic, and translational insights, framing CHIP as an emerging causal factor in cardiometabolic disease and as a promising target for precision medicine in aging populations.

Clonal hematopoiesis of indeterminate potential (CHIP), driven by leukemia-related somatic mutations in hematopoietic stem cells, previously recognized as a major risk factor for hematological malignancies, has now emerged as a potent risk factor for chronic inflammation and diverse non-hematologic diseases. CHIP-associated DNA methyltransferase 3 alpha (DNMT3A), tet methylcytosine dioxygenase 2 (TET2), and additional sex combs like 1 (ASXL1) mutations alter epigenetic programs, skew myelopoiesis, and increase proinflammatory cytokines, resulting in chronic inflammation and immune imbalance. This review integrates mechanistic insights with clinical evidence to delineate CHIP’s roles in solid tumors, cardiovascular disorders, and metabolic dysregulation, with an extended discussion of renal dysfunction and neurodegenerative conditions. Furthermore, we also discuss CHIP’s diagnostic and therapeutic impacts across multiple disease contexts, advocating for mutation-specific diagnostic paradigms to guide therapeutic interventions.

Clonal hematopoiesis of indeterminate potential (CHIP), marked by age‐related somatic mutations in hematopoietic cells, has been linked to cardiovascular disease. Given its shared risk profile with venous thromboembolism (VTE), we evaluated the association between CHIP and VTE.

Chronic kidney disease (CKD) afflicts over 10% of US adults, with its prevalence increasing sharply with age. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, genetically heterogeneous blood cell disorder characterized by the age-related clonal expansion of hematopoietic cells driven by leukemogenic somatic mutations yet without hematologic malignancy or dysplasia. While CHIP is a strong risk factor for future hematologic malignancy (estimated at ∼0.5% per year, compared to <0.1% for those without CHIP), it is also linked to twofold higher cardiovascular disease in epidemiologic, cell-based, and murine studies. However, more recent work has implicated CHIP with renal outcomes such as chronic kidney disease as well as acute kidney injury, independent of traditional risk factors. This review covers the observations and proposed hypotheses linking CHIP and kidney disease. The review also underscores the need for further research to elucidate the distinct pathways through which CHIP may contribute to CKD and its comorbidities, considering the heterogeneity within CKD stages and etiologies, as well as whether CHIP is a causal driver of kidney disease or a marker of aging and comorbidity. Finally, we discuss the potential of anti-inflammatory treatments to mitigate CHIP's adverse effects on kidney health, aiming to improve management strategies for patients with CHIP-associated kidney diseases.

Clonal hematopoiesis of indeterminate potential (CHIP) is a non-malignant state characterized by hematopoietic stem cells exhibiting clonality driven by acquired mutations during aging. Using next generation sequencing (NGS), it has been reported that the prevalence of CHIP increases exponentially with age. Thus far, epigenetic mutations including DNMT3A, TET2, and ASXL1 are the most common mutations identified in driving CHIP. CHIP is considered a pre-malignant state, however with reports of its associations with non-malignant disease states, the clinical impact of CHIP has been of great interest, in particular its effect on the renal and cardiac systems. CHIP has been associated with a higher rate of estimated glomerular filtration rate (eGFR) decline and increased risk of acute kidney injury (AKI). CHIP and its driver mutations, have also been shown to increase cardiovascular disease and atherosclerosis through various inflammatory pathways. In this review, we discuss the pathophysiology of CHIP through aging, its impact on kidney disease, and implications on cardiovascular health. We also compare CHIP to another pre-malignant clonal disorder, monoclonal gammopathy of undetermined significance (MGUS).

Aortic valve stenosis (AVS) is the most common valvular heart disease that was considered, for a long time, a passive degenerative disease due to physiological aging. More recently, it has been recognized as an active, modifiable disease in which many cellular processes are involved. Nevertheless, since aging remains the major risk factor for AVS, a field of research has focused on the role of early (biological) aging and its dependent pathways in the initiation and progression of AVS. Telomeres are regions at the ends of chromosomes that are critical for maintaining genome stability in eukaryotic cells. Telomeres are the hallmarks and molecular drivers of aging and age-related degenerative pathologies. Clonal hematopoiesis of indeterminate potential (CHIP), a condition caused by somatic mutations of leukemia-associated genes in individuals without hematologic abnormalities or clonal disorders, has been reported to be associated with aging. CHIP represents a new and independent risk factor in cardiovascular diseases, including AVS. Interestingly, evidence suggests a causal link between telomere biology and CHIP in several pathological disorders. In this review, we discussed the current knowledge of telomere biology and CHIP as possible mechanisms of aortic valve degeneration. We speculated on how a better understanding of the complex relationship between telomere and CHIP might provide great potential for an early diagnosis and for developing novel medical therapies to reduce the constant increasing health burden of AVS.

In clonal hematopoiesis of indeterminate potential (CHIP), subpopulations of blood cells carrying somatic mutations expand as the individual ages, and this expansion may elevate risk of blood cancers as well as cardiovascular disease. Individuals at higher risk of CHIP and therefore of CHIP-associated disease can be identified through mutational profiling, and the apparently central role of inflammation in CHIP-associated disease has emerged as a potential therapeutic target. While CHIP is often associated with negative health outcomes, emerging evidence suggests that some CHIP-related mutations may also exert beneficial effects, indicating a more complex role in human health. This review examines current understanding of the epidemiology and clinical significance of CHIP and the role of inflammation in driving its association with disease risk. It explores the mechanisms linking CHIP to inflammation and risk of cardiovascular and other diseases, as well as the potential of personalizing therapies against those diseases for individuals with CHIP.

The recent characterization of clonal hematopoiesis in a large segment of the aging population has raised tremendous interest and concern alike. Mutations have been documented in genes associated with hematological cancers and in non‐driver candidates. These mutations are present at low frequency in the majority of individuals after middle‐age, and principally affect the epigenetic modifiers DNMT3A and TET2. In 10%–40% of cases, the clone will progress to meet the diagnostic criteria for Clonal Hematopoiesis of Indeterminate Potential, which is associated with an increased risk of hematological cancer and cardiovascular mortality. Blood cell parameters appear unmodified in these individuals, but a minority of them will develop a hematologic malignancy. At this time, the factors put forward as potentially influencing the risk of cancer development are clone size, specific gene, specific mutation, and the number of mutations. Specific stress on hematopoiesis also gives rise to clonal expansion. Genotoxic exposure (such as chemotherapy), or immune attack (as in aplastic anemia) selects/provides a fitness advantage to clones with a context‐specific signature. Clonal hematopoiesis offers a new opportunity to understand the biology and adaptation mechanisms of aging hematopoiesis and provides insight into the mechanisms underlying malignant transformation. Furthermore, it might shed light on common denominators of age‐associated medical conditions and help devise global strategies that will impact the prevention of hematologic cancers and promote healthy aging. Stem Cells 2018;36:1287–1294

PURPOSE OF REVIEW While advanced age is the major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), we have a poor understanding of how aging promotes the progression of this disease. Recent evidence suggests that the age-dependent accumulation of somatic mutations in hematopoietic cells may represent a new causal risk factor for ASCVD. RECENT FINDINGS A hallmark of aging is the accumulation of somatic DNA mutations in all tissues of the body. Accordingly, evidence shows that hematopoietic stem/progenitor cells accumulate somatic mutations as a function of age in nonsymptomatic individuals. When these mutations occur in driver genes that provide a selective advantage to the hematopoietic stem/progenitor cells, they undergo a clonal expansion and progressively give rise to blood leukocytes that harbor these mutations. This phenomenon, referred to as clonal hematopoiesis, has been associated with the increased risk of mortality, hematologic malignancy, ASCVD, and related diseases. Notably, many individuals exhibiting clonal hematopoiesis carry single 'driver' mutations in preleukemic genes including DNA methyltransferase 3a, ten-eleven translocation 2, additional sex combs like 1, and Janus kinase 2. Experimental studies show that these mutations in some of these genes can alter the inflammatory properties of the leukocyte and contribute to the pathogenesis of ASCVD. SUMMARY We review recent epidemiological and experimental findings on the association between age-related clonal hematopoiesis and ASCVD by focusing on prevalent driver gene mutations.

Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematological malignancies, accumulating evidence has led to its broad recognition as a relevant factor in various age-related nonmalignant diseases, particularly those with inflammatory components, such as cardiovascular disease, autoimmune disorders, and solid tumors. Notably, the increased overall mortality associated with CH is primarily driven by cardiovascular complications rather than hematological malignancies. Among CH-associated genes, ASXL1 mutations are distinguished by their strong associations with adverse clinical outcomes and pro-inflammatory signatures. However, compared to TET2 and DNMT3A, the molecular and pathological implications of ASXL1-mutated CH remain underexplored. Recent studies have expanded the disease spectrum of ASXL1 mutations beyond hematological malignancies, implicating them in clonal expansion and systemic inflammation. This review aims to summarize the current epidemiological and experimental insights into ASXL1-mutated CH, focusing on its potential contributions to inflammation-associated diseases. By integrating clinical observations and emerging mechanistic data, we highlight the urgent need for deeper investigation into ASXL1-driven CH and its systemic consequences beyond hematological transformation.

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The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.

Cardiovascular disease (CVD) is a major driver of mortality and declining health worldwide. Cardiovascular diseases (CVD) is the most common cause of morbidity and mortality globally. Although dyslipidemia, smoking, diabetes, hypertension and obesity are some well-known causes of CVD, the overlapping genetic pathways between other diseases and those affecting cardiovascular health have been overlooked. In the past decade, mutations in TET2, DNMT3A, ASXL1, and JAK2 are found to cause clonal hematopoiesis of intermediate potential (CHIP), a disease associated with age-related haematological malignancies without the presence of cytopenias or dysplasia. Coronary artery disease, heart failure, aortic stenosis, and arrhythmias have been shown to be associated with the presence of CHIP mutations. Addressing the association between CHIP could significantly reduce residual risk patients with CVD. The link between CHIP and CVD can potentially be addressed through inhibitors of inflammasomes, antagonists in the interleukin pathway, or direct antagonists of CHIP mutations.

Autologous stem cell transplantation (ASCT) after high-dose chemo-therapy (HDCT) is an option of consolidation therapy in patients with AML, lymphoma, or myeloma. Clonal hematopoiesis (CH) is a premalignant state, associated with an increased risk of hematological cancer. The incidence of CH in patients with AML, myeloma, and lymphoma and its effect on the outcome after HDCT/ASCT remain poorly studied. Here we screened 142 patients treated with HDCT/ASCT between 2002 and 2021 at Bern University Hospital for somatic gene mutations in ASXL1, DNMT3A, JAK2, TET2, and TP53. CH-associated somatic gene mutations were detected in 14/31 AML patients (45%), 13/64 myeloma patients (20%), and 9/47 lymphoma patients (19%). Clinical characteristics, treatment modalities, and responses to treatment were similar in patients with and without CH. Patients with CH-associated gene mutations had higher relapse rates and reduced progression free survival, most evident in lymphoma patients (p = 0.007). Overall survival tended to be shorter in lymphoma patients with CH-associated mutations (p = 0.078), whereas this was not observed in AML and myeloma patients. Survival in lymphoma patients with CH was inferior, which may have an impact on post-transplant surveillance strategies in the future. In contrast, survival outcomes were not associated significantly with CH in AML and myeloma patients in our study. Longer follow-ups and larger cohorts will be needed to validate our observations.

Introduction Clonal hematopoiesis of indeterminate potential (CHIP) occurs when a hematopoietic stem cell undergoes clonal proliferation as a part of normal aging. Commonly involved genes include DNMT3A, TET2, ASXL1, and JAK2 and rarely, KRAS, PIK3CAand EGFR. Most people are asymptomatic, but it can seldom lead to myelodysplastic syndrome and acute myeloid leukemia. More commonly, these disorders lead to a proinflammatory state, increasing the risk of cardiovascular disease at similar rates as metabolic risk factors. In recent years, the association with non-hematological malignancies, especially gastrointestinal cancers, has been studied. In the review, we have summarized the association of GI malignancies with CHIP and the mutations that increase such risk. Methods Among patients with CHIP (P), the risk of gastrointestinal malignancy (O) compared to individuals without CH (C), based on observational studies (E) was studied. PubMed, Scopus, Google Scholar, Embase, Cochrane Library, Web of Science, and Crossref were explored for observational studies exploring the association. After excluding duplicates, case reports, and animal studies, 7 studies were selected. From the seven studies, only 5 exclusively focused on gastrointestinal malignancy. It included 3 case-control and 2 cohort studies. PRISMA guidelines were followed, and the Cochrane risk of bias tool was then used for the selected studies, indicating heterogeneity due to different study types. Results The combined prevalence of CHIP in GI malignancies, including HCC, CRC, and pancreatic adenocarcinoma across the cohort studies, is approximately 19.7%. The pooled odds ratio of CHIP is approximately 1.24, with a 95% confidence interval of 1.11 to 1.39, suggesting a modest but statistically significant relationship. TET2 showed a consistently elevated risk across CRC and HCC. ATM had a strong association with CRC. ASXL1 and DNMT3A were associated with gastric cancer, with odds of around 2. Females and older individuals were at a higher risk. Discussion The possible correlation between CHIP and gastrointestinal cancer is a proinflammatory state and an impaired T cell function. TET2 mutation in macrophage and DNMT3 mutation in mast cells induce IL-6, IL-8, and TNF-alpha activity. This has been associated with inflammation in the gut lining, H. pylori, and elevation in transaminases with fibrosis. These have been risk factors in GI malignancies, hence indicating an indirect causation. However, the incidence is higher in older individuals. Age might be a confounding factor since CHIP and malignancies both occur in the older population, and a higher incidence amongst that group reflects the same. Conclusion CHIP has been associated with GI malignancies in previous studies and our review. Causation has been implicated by a pro-inflammatory state and indirect risks. However, limitations, including confounding with age, need to be explored. Currently, no guidelines exist to test for CHIP or early surveillance in people with CHIP for GI malignancies. Hence, more prospective studies with age-stratified groups need to be performed to determine the link and tailor future actions accordingly.

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Clonal hematopoiesis (CH) is the expansion of clones from a single hematopoietic stem cell (HSC) in the bone marrow. Clonal hematopoiesis of indeterminate potential (CHIP) refers to CH defined by the presence of pre-leukemic driver mutations in at least 2% of alleles in sequenced peripheral blood. This phenomenon is, by definition, associated not only with the future development of acute myeloid leukemia but also with non-malignant conditions, including cardiovascular disease. However, the underlying molecular mechanisms for CH in non-malignant diseases, such as cardiovascular disease, are not fully explained. Certain subtypes of CHIP may give rise to proinflammatory immune cells, which, in turn, may promote atherosclerosis progression. Key subtypes of CHIP include mutations in genes encoding epigenetic regulators DNMT3A (DNA methyltransferase 3A), TET2 (ten-eleven translocation methylcytosine dioxygenase 2), and ASXL1 (associated sex combs-like 1), as well as mutations in the gene encoding hematopoietic cytokine signaling: JAK2 (Janus kinase 2). The aim of this review is to summarize the current knowledge of CHIP and its association with inflammation and cardiovascular risk factors.

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Cardiovascular and oncological diseases represent the global major causes of death. For both, a novel and far-reaching risk factor has been identified: clonal hematopoiesis (CH). CH is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy. The most commonly affected genes are TET2 , DNMT3A , ASXL1 and JAK2 . By the age of 70, at least 20–50% of all individuals carry a CH clone, conveying a striking clinical impact by increasing all-cause mortality by 40%. This is due predominantly to a nearly two-fold increase of cardiovascular risk, but also to an elevated risk of malignant transformation. Individuals with CH show not only increased risk for, but also worse outcomes after arteriosclerotic events, such as stroke or myocardial infarction, decompensated heart failure and cardiogenic shock. Elevated cytokine levels, dysfunctional macrophage activity and activation of the inflammasome suggest that a vicious cycle of chronic inflammation and clonal expansion represents the major functional link. Despite the apparently high impact of this entity, awareness, functional understanding and especially clinical implications still require further research. This review provides an overview of the current knowledge of CH and its relation to cardiovascular and hematological diseases. It focuses on the basic functional mechanisms in the interplay between atherosclerosis, inflammation and CH, identifies issues for further research and considers potential clinical implications.

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. It is considered to be a premalignant state that predisposes individuals to an increased risk of cancers. Recently, emerging evidence has demonstrated a strong association between CH and both the incidence and mortality of cardiovascular diseases (CVD), with the relative risks being comparable to those attributed to traditional cardiovascular risk factors. In addition, CH has been suggested to play a role in CVD and anti-cancer treatment-related cardiotoxicity amongst cancer survivors. Moreover, certain forms of chemotherapy and radiation therapy have been shown to promote the clonal expansion of specific CH-related mutations. Consequently, CH may play a substantial role in the realm of cardio-oncology. In this review, we discuss the association between CH with cancer and CVD, with a special focus on anti-cancer treatment-related cardiotoxicity, discuss possible future research avenues and propose a systematic approach for clinical practice.

Importance Clonal hematopoiesis (CH) has been recently described as a novel driver for cancer and cardiovascular disease (CVD). Clonal hematopoiesis is a common, age-associated disorder marked by expansion of hematopoietic clones carrying recurrent somatic mutations. Current literature suggests that patients with CH have a higher risk of subsequent hematological malignant conditions and mortality attributable to excess CVD. This review discusses the association of cancer with CVD with CH as a potential unifying factor. Observations The prevalence of CH varies based on the sequencing depth, diagnostic criteria, and patient age and ranges from less than 1% in those younger than 40 years to more than 15% to 20% in those 90 years and older. Clonal hematopoiesis is associated with a 0.5% to 1.0% absolute annual risk of hematological malignant condition and a 2-fold to 4-fold higher risk of coronary artery disease, stroke, and CVD deaths, independent of traditional cardiovascular risk factors. In fact, CH appears to have a relative risk similar to that of traditional cardiovascular risk factors for CVD. Experimental studies suggest that the link between CVD and CH is causal, with inflammation as 1 potential mechanism. There may be also a link between CH and CVD in survivors of cancer; however, data to support this association are currently limited. Conclusions and Relevance Clonal hematopoiesis represents a premalignant state, with carriers having an increased risk of hematological malignant conditions. Although most carriers will not develop a malignant condition, CH confers an increased risk of CVD, possibly via inflammation. Clonal hematopoiesis may also contribute to CVD in survivors of cancer, although this hypothesis requires validation. Clinically, as advanced sequencing techniques become available, CH may pave the way for precision medicine in the field of cardio-oncology.