Tet2 age-associated somatic mutations impair megakaryopoiesis, drive platelet reactivity and enhance thrombosis 3105

Description Aging is accompanied by the accumulation of somatic mutations in hematopoietic stem cells and their blood cell progeny, referred to as clonal hematopoiesis of indeterminate potential (CHIP). Notably, loss-of-function mutations in the epigenetic modulator TET2 are the second most prevalent driver of CHIP and have been identified as a unilateral driver of CVD. Aging is the strongest risk factor for both CHIP, CVD, and platelet dysfunction. Platelets are circulating blood cells, derived from megakaryocytes (MKs) in the bone marrow. Platelets are crucial for normal hemostasis and thus play a substantial role in driving the thrombotic complications of CVD. Using murine models with hematopoietic (Mx1Cre) and MK-lineage (PF4Cre) targeted Tet2 deletion, our data show that in a chimeric setting Tet2KO platelets are hyperreactive and increase the reactivity of unmutated bystander platelets. We also observed an increase in arterial thrombus formation in (PF4Cre) Tet2KO chimeric mice harboring 10-20% mutant platelets. This suggests that Tet2 deletion in platelets is a sufficient stand-alone driver of thrombus formation. Platelet accumulation was also elevated by > 40%, indicating that a minority of mutated platelets is sufficient to enhance thrombosis. Tet2 deficient MKs also display significant cytoskeletal alterations and platelet production deficiencies. This work suggest TET2 LOF mutations may contribute to the platelet dysfunction and enhanced thrombotic risk reported in aging. Funding Sources American Society of Hematology Scholar Award Topic Categories Hematopoiesis and Immune System Development (HEM)