Clonal hematopoiesis driver mutations: molecular mechanisms and clinical implications - inclusive fitness of pre-leukemic hematopoietic stem and progenitor cells through pro-inflammatory features of their progeny

Abstract

Clonal hematopoiesis (CH) is driven by the age-associated expansion of hematopoietic stem and progenitor cells (HSPCs) that harbor somatic driver mutations; however, the mechanisms underlying their long-term persistence remain incompletely understood. This review frames CH through the lens of inclusive fitness, proposing that mutant pre-leukemic HSPCs enhance their evolutionary success not only through intrinsic self-renewal advantages, but also via indirect effects mediated by their differentiated progeny. We synthesize evidence showing that mutant immune cells promote inflammatory microenvironments that selectively impair wild-type HSCs while reinforcing mutant self-renewal, establishing self-sustaining feedback loops that shape clonal dynamics and systemic disease risk.