摘要Aging-elevated DNMT3A R882H-driven clonal hematopoiesis(CH)is a risk factor for myeloid malignancies remission and overall survival.Although some studies were conducted to investi-gate this phenomenon,the exact mechanism is still under debate.In this study,we observed that DNMT3A R878H bone marrow cells(human allele:DNMT3A R882H)displayed enhanced reconstitu-tion capacity in aged bone marrow milieu and upon inflammatory insult.DNMT3A R878H protects he-matopoietic stem and progenitor cells from the damage induced by chronic inflammation,especially TNFα insults.Mechanistically,we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNFα insults.Briefly,we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis,which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malig-nancies with aging.