Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis

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 DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNF alpha insults. Mechanistically, we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNF alpha 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 malignancies with aging. (c) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Aging-related DNMT3A R882H-driven clonal hematopoiesis is a risk factor for myeloid malignancies remission and overall survival. The study found that DNMT3A R878H bone marrow cells exhibit enhanced reconstitution capacity in aged bone marrow environment and protection against inflammatory insults. Mechanistically, R878H cells showed compromised necroptosis signaling in response to proliferation stress and TNF alpha insults, providing insights into the molecular mechanism driving clonal hematopoiesis.