Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis.
10.1016/j.apsb.2021.09.015
- Author:
Min LIAO
1
;
Ruiqing CHEN
1
;
Yang YANG
1
;
Hanqing HE
1
;
Liqian XU
1
;
Yuxuan JIANG
1
;
Zhenxing GUO
2
;
Wei HE
1
;
Hong JIANG
3
;
Jianwei WANG
1
Author Information
1. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
2. Department of Hematology/Oncology, First Hospital of Tsinghua University, Beijing 100016, China.
3. Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
- Publication Type:Journal Article
- Keywords:
Aging;
Clonal hematopoiesis;
DNMT3A R882H;
Hematopoietic stem cells;
Inflammation;
Necroptosis;
TNFα
- From:
Acta Pharmaceutica Sinica B
2022;12(2):678-691
- CountryChina
- Language:English
-
Abstract:
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.
