Details

Autor(en) / Beteiligte

• Liao, Min
• Chen, Ruiqing
• Yang, Yang
• He, Hanqing
• Xu, Liqian
• Jiang, Yuxuan
• Guo, Zhenxing
• He, Wei
• Jiang, Hong
• Wang, Jianwei

Titel

Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis

Ist Teil von

• Acta pharmaceutica Sinica. B, 2022-02, Vol.12 (2), p.678-691

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2022

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. With aging, hematopoietic stem cells accumulate DNMT3A mutation with necroptosis resistance which results in clonal hematopoiesis, and this process can be aggravated by inflammation challenge. [Display omitted]