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JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis.
Experimental Hematology 2018 March
Clonal hematopoiesis of aging and indeterminate potential (ARCH or CHIP), driven mainly by mutations in DNMT3A and TET2, is an emerging public health issue, affecting at least 10-15% of adults older than 65 years. CHIP is associated with increased risks of de novo and therapy-related hematological neoplasms and serves as a reservoir for leukemic relapse. CHIP is also associated with increased all-cause mortality and risk of cardio-metabolic disease. The latter association may be explained, at least in part, by the effects of inactivating mutations in TET2 on progeny macrophages. We and others have shown recently that TET2-deficient macrophages are hyperinflammatory and this may exacerbate processes such as atherosclerosis. We postulated an inflammatory state associated with TET2 inactivation and/or unhealthy aging may also favor TET2-mutant hematopoietic stem and progenitor cell (HSPC) expansion. Herein, we demonstrate a clonogenic advantage for Tet2-knockout murine and TET2-mutant human HSPCs in an in vitro environment that contains the proinflammatory cytokine tumor necrosis factor-alpha (TNFα). This phenotype emerges on chronic TNFα exposure and is associated with myeloid skewing and resistance to apoptosis. To our knowledge, this is the first evidence to suggest that TET2 mutations promote clonal dominance with aging by conferring TNFα resistance to sensitive bone marrow progenitors while also propagating such an inflammatory environment. Normalizing the immune environment may present a novel strategy to control or eradicate mutant CHIP clones.
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