期刊
SCIENCE ADVANCES
卷 7, 期 52, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abj6877
关键词
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资金
- National Key Research and Development Program of China [2017YFA0106300]
- National Natural Science Foundation of China [81600086, 81770100]
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81621004]
- Projects of International Cooperation and Exchanges NSFC [81820108025]
- Fundamental Research Funds for the Central Universities [50000-31620026]
ATF4 deficiency leads to severe HSC defects with aging-like phenotype, affecting HSC function by regulating HIF1α and p16(Ink4a), and delaying leukemogenesis.
Aging of hematopoietic stem cells (HSCs) directly contributes to dysfunction of hematopoietic and immune systems due to aging-associated alterations in HSC features. How the function of adult HSCs is regulated during aging so that relevant pathologic abnormalities may occur, however, remains incompletely understood. Here, we report that ATF4 deficiency provokes severe HSC defects with multifaceted aging-like phenotype via cell-autonomous mechanisms. ATF4 deletion caused expansion of phenotypical HSCs with functional attrition, characterized by defective repopulating and self-renewal capacities and myeloid bias. Moreover, the ATF4(-/-) HSC defects were associated with elevated mitochondrial ROS production by targeting HIF1 alpha. In addition, loss of ATF4 significantly delayed leukemogenesis in the MLL-AF9-induced leukemia model. Mechanistically, ATF4 deficiency impaired HSC function with aging-like phenotype and alleviated leukemogenesis by regulating HIF1 alpha and p16(Ink4a). Together, our findings suggest a possibility of developing new strategies for the prevention and management of HSC aging and related pathological conditions.
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