Tet2-associated extrinsic factors shape healthy hematopoiesis 4697

Abstract Description Somatic mutations in hematopoietic stem and progenitor cells (HSPCs) are a hallmark of aging and contribute to immune dysregulation and inflammation. While much research has primarily focused on the selective advantage of mutant HSPCs, the effects of the inflammatory microenvironment on non-mutated cells remain poorly understood. Our study investigates how Tet2 mutations influence non-mutated HSPCs in a non-irradiated, chimeric transplant model; bone marrow was collected at several months post-transplant to assess changes in HSPC population dynamics. Our results show that both Tet2KO and mutant-exposed HSPCs had an increased frequency of myeloid-biased progenitor, with a corresponding decrease in lymphoid-biased progenitors. Interestingly, granulocyte-monocyte progenitors were expanded by frequency in Tet2KO and decreased in mutant-exposed HSPC populations. Transcriptomic analysis of HSPCs (Lineage– Sca1+ ckit+) showed that mutant-exposed myeloid progenitors were enriched in TNFa-mediated response, whereas Tet2KO cells upregulated pro-inflammatory cytokines such as IL-6 and IFNg. Collectively, these results suggest that Tet2KO progenitors have an altered response to the CHIP environment and increased differentiation advantage. Ongoing studies aim to separate the roles of intrinsic cellular responses versus extrinsic inflammation, with the goal of identifying actionable targets for future therapeutic interventions and alleviating pathologies in aging and disease. Funding Sources 5T32AR069516-07, Marks Foundation Endeavor Grant Topic Categories Hematopoiesis and Immune System Development (HEM)