Clonal hematopoiesis as a context-dependent modifier of organ-specific disease: Evidence, mechanisms, and translational boundaries

Abstract

Clonal hematopoiesis (CH) arises when age-associated somatic mutations confer a proliferative advantage on hematopoietic stem and progenitor cells, producing expanded clonal blood cell populations. Clonal hematopoiesis of indeterminate potential (CHIP) is clinically defined by a variant allele fraction (VAF) of ≥ 2% in individuals without hematologic malignancy or otherwise unexplained persistent cytopenia (Jaiswal et al., 2014; Jaiswal and Ebert, 2019). Although CHIP was first viewed mainly as a premalignant precursor state, population cohorts and experimental models indicate that CH can also modify non-malignant disease risk, most reproducibly in atherosclerotic cardiovascular disease (Jaiswal et al., 2017; Weeks and Ebert, 2023). In this review, we use “systemic modifier” in a restricted sense: CH should not be interpreted as a uniform cause of multiorgan disease, but as a hematopoietic state that may alter inflammatory thresholds, myeloid output, thrombo-inflammatory tone, and tissue responses under permissive genotype-, clone-size-, exposure-, and organ-specific conditions. We examine how biased myeloid output, NLRP3 inflammasome activation, trained immunity-like epigenetic priming, NETosis, chemokine-guided myeloid recruitment, and immune-stromal interactions connect hematopoietic clones to disease-context-specific phenotypes. Soluble inflammatory mediators and cellular trafficking currently have the strongest mechanistic support. Extracellular vesicles and metabolic intermediates are treated as plausible but incompletely validated routes, particularly at physiologic clone sizes and in low-VAF CH. We then assess cardiovascular, hepatic, pulmonary, skeletal, renal, and neurological disease modules, and consider infectious-inflammatory and tumor-related settings as contextual modifiers, while distinguishing established mechanisms from plausible hypotheses and preliminary observations. Finally, we discuss translational opportunities, including IL-1β/NLRP3 and thrombo-inflammatory targeting, together with safety boundaries imposed by infection risk, systemic immunosuppression, and non-specific metabolic toxicity.