Clonal hematopoiesis shapes tissue immunity

Somatic mutations acquired by hematopoietic stem cells can give rise to clonal hematopoiesis (CH), generating genetically altered immune cells whose effects extend beyond the bone marrow and circulating blood. Understanding how these cells enter tissues and respond to local challenges is essential to explain the consequences of CH beyond hematological malignancy. Studies of CH-associated mutations in the epigenetic regulators TET2 and DNMT3A highlight the connection between stem-cell selection and altered immune function. 
Experimental approaches combining genetically engineered primary human hematopoietic stem cells, humanized mouse models and molecular profiling reveal altered monocyte–macrophage differentiation and infiltration of mutant immune progeny into peripheral tissues and the tumor microenvironment. Notably, TET2-mutant stem and progenitor cells exhibit epigenetic silencing of AP-1 transcription factors and reduced inflammatory responsiveness, whereas their myeloid descendants display exaggerated inflammatory activation. This dichotomy helps explain how inflammatory stress can favor the expansion of mutant stem cells while their progeny amplify inflammation. Together, these findings connect the somatic evolution of hematopoiesis with altered tissue immunity, with implications for tissue homeostasis, responses to infection and tumor progression.