Alexander G. Bick

From the 2026 National Summit on Hematologic Cancers

Line plots showing change in VAF for all patients with detectable DNMT3A mutations, colored by clonal behavior.

Clonal haematopoiesis (CH) activates inflammation and increases the risk of atherosclerosis^1,2. Whether lifestyle alters CH clone expansion or the phenotypic programming of CH mutant cells, thereby affecting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, Trp53 and Dnmt3a, we demonstrate mutation-dependent responses to sleep and exercise in CH and show that mutant cells are uniquely sensitive to lifestyle. In two human datasets, moderate-to-vigorous physical activity was associated with lower prevalence of non-DNMT3A-driven CH. In atherogenic mice with Jak2^V617F or Tet2 loss of function (LOF), but not Trp53 LOF or Dnmt3a^R878H CH, uninterrupted sleep or exercise curtails clone expansion. In CH with the Jak2^V617F mutation, sleep and exercise reduces clone expansion by selectively reprogramming mutant, but not cohabitant wild type, haematopoietic progenitor cells towards antiproliferative and metabolically healthy phenotypes by tempering bone marrow macrophage-haematopoietic progenitor cell IL-1β signalling. Sleep or exercise also lessens Jak2^V617F-driven, Tet2 LOF-driven and Trp53 LOF-driven, but not Dnmt3a^R878H-driven, atherosclerosis by locally reprogramming mutant vascular macrophages, independent of peripheral clone dynamics. In Jak2^V617F, but not adjacent wild type, aortic macrophages, uninterrupted sleep blunts CLEC4E-dependent inflammasome activation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1⁺ neurons in the locus coeruleus, raising the levels of peripheral noradrenaline, which signals through adrenergic receptor β2 (ADRβ2) whose expression is preserved by exercise in Jak2^V617F, but not cohabitant wild type, aortic macrophages, selectively repressing their inflammatory programming and atherosclerosis. Our findings establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant haematopoietic progenitor cells and macrophages to maintain cardiovascular health.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women’s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] ≥ 2%) and large CHIP (VAF ≥ 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non- DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non- DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that increases risk for cardiovascular disease. However, its relationship with stroke remains uncertain. METHODS: To resolve these conflicting findings, we analyzed genomic and clinical data from 800 160 participants with genetic sequencing and medical records across 3 large-scale cohorts: the Vanderbilt BioVU biobank (United States; enrollment 2007–2022), the National Institutes of Health All of Us Research Program (United States; enrollment 2018–2023), and the UK Biobank (United Kingdom; enrollment 2006–2010). The median follow-up time was 4.4 years (interquartile range, 1.8–10.2) in BioVU, 1.9 years (interquartile range, 0.4–3.9) in All of Us, and 12.4 years (interquartile range, 11.7–13.1) in UK Biobank. Stroke events were identified and classified as ischemic or hemorrhagic using International Classification of Diseases codes. Subgroup analyses were conducted by driver gene, clone size, sex, and menopausal status. Genetically predicted levels of 27 cytokines were assessed for modification of CHIP-associated stroke risk. RESULTS: CHIP was associated with increased risk of incident stroke in the meta-analysis (hazard ratio [HR], 1.20 [95% CI, 1.14–1.27]; P =1.92×10 ⁻¹⁰ ). This association was observed for ischemic (HR, 1.18) and hemorrhagic (HR, 1.25) stroke subtypes. Gene-specific analyses showed strong associations for JAK2 (HR, 2.52) and TET2 (HR, 1.23). DNMT3A demonstrated weak but significant associations (HR, 1.13). CHIP was associated with stroke risk in both sexes; however, among women, the association was evident in postmenopausal (HR, 1.49 [95% CI, 1.16–1.92]; P =1.91×10 ⁻³ ) but not in premenopausal participants (HR, 0.70 [95% CI, 0.36–1.43]; P =0.33). Among participants with CHIP, but not among participants without CHIP, genetically predicted levels of IL-1RAP (interleukin-1 receptor accessory protein) were predictive of risk for stroke, suggesting IL-1RAP as a modifier of the CHIP-associated risk for stroke. CONCLUSIONS: Our large-scale, multicohort study establishes CHIP as a determinant of incident stroke risk and IL (interleukin)-1–mediated inflammation as a targetable pathway to reduce this risk.

Background: Small particulate matter air pollution (PM2.5) is a recognized driver of non–small cell lung cancer (NSCLC), including in nonsmoking individuals. Inhaled PM2.5 recruits proinflammatory macrophages to the air-lung interface, which promotes malignant lung epithelial cell growth and progression to overt cancer. Smoking is recognized to potentiate this process, though no factors potentiating risk among nonsmoking individuals have been identified. We sought to determine whether clonal hematopoiesis of indeterminate potential (CHIP), a common age-related condition characterized by hyperinflammatory macrophages, synergizes with PM2.5 to promote NSCLC in nonsmoking individuals. Methods: This study was conducted with data from over 650 000 people in the UK Biobank and All of Us cohorts. PM2.5 exposures were derived based on geospatial estimates and linked with participant residences. The gene-environment interaction between CHIP status and PM2.5 exposures on the risk of incident NSCLC was assesed using Cox proportional hazard regression and meta-analyzed across cohorts. Results: In meta-analysis, CHIP was associated with a greater risk of NSCLC in never-smoking participants (hazard ratio [HR] = 1.76, 95% CI = 1.07 to 2.89). This risk is exacerbated in the setting of above-median PM2.5 levels (HR = 2.51, 95% CI = 1.55 to 4.05; P = .02 for interaction). The CHIP-PM2.5 interaction is also associated with elevated markers of systemic inflammation. Conclusion: Together, these results suggest that CHIP and PM2.5 form a novel somatic gene-environment interaction promoting inflammation and NSCLC tumorigenesis in nonsmoking individuals.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have pronounced elevations in risk of myeloid and lymphoid malignancies (HRs>40), particularly when CHIP and mCAs overlap genomically. Our findings indicate CH co-occurrences are selected for in the aging population and identify CH clones with notable implications for future malignancy risk.

This cohort study explores the association between clonal hematopoiesis of indeterminate potential and risk of incident pericarditis and myocarditis among participants in 2 large US biobanks.