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 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 malignancies with aging.

衰老升高的 DNMT3A R882H 驱动的克隆性造血 (CH) 是髓系恶性肿瘤缓解和总生存期的危险因素。尽管进行了一些研究来调查这种现象，但确切的机制仍在争论中。在这项研究中，我们观察到 DNMT3A R878H 骨髓细胞（人类等位基因：DNMT3A R882H）在老年骨髓环境和炎症损伤中表现出增强的重建能力。DNMT3A R878H 保护造血干细胞和祖细胞免受慢性炎症引起的损伤，尤其是 TNF α损伤。从机制上讲，我们发现 RIPK1-RIPK3-MLKL 介导的坏死性凋亡信号在 R878H 细胞中因增殖应激和 TNF α而受到损害侮辱。简而言之，我们阐明了驱动基于 DNMT3A R878H 的克隆性造血的分子机制，这提高了治疗 DNMT3A R882H 驱动的克隆性造血和随年龄增长的髓系恶性肿瘤的临床价值。