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 investigate this phenomenon,the exact mechani...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 investigate this phenomenon,the exact mechanism is still under debate.In this study,we observed that DNMT3 A R878 H bone marrow cells(human allele:DNMT3 A R882 H)displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult.DNMT3 A R878 H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation,especially TNFa insults.Mechanistically,we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878 H cells in response to proliferation stress and TNFa insults.Briefly,we elucidated the molecular mechanism driving DNMT3 A R878 H-based clonal hematopoiesis,which raises clinical value for treating DNMT3 A R882 H-driven clonal hematopoiesis and myeloid malignancies with aging.展开更多
基金the Beijing Advanced Innovation Center for Structural Biology and the Tsinghua-Peking Center for Life Sciences for facility and financial supportsupported by grant numbers 2018YFA0800200,2017YFA0104000,91849106,Z200022,Z181100001818005 and 81870118 to Jianwei Wang from the National Key R&D Program of China or the Beijing Municipal Science&Technology Commission and the National Natural Science Foundation of China。
文摘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 investigate this phenomenon,the exact mechanism is still under debate.In this study,we observed that DNMT3 A R878 H bone marrow cells(human allele:DNMT3 A R882 H)displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult.DNMT3 A R878 H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation,especially TNFa insults.Mechanistically,we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878 H cells in response to proliferation stress and TNFa insults.Briefly,we elucidated the molecular mechanism driving DNMT3 A R878 H-based clonal hematopoiesis,which raises clinical value for treating DNMT3 A R882 H-driven clonal hematopoiesis and myeloid malignancies with aging.
