Human hematopoietic stem cell vulnerability to ferroptosis

被引：76

作者：

Zhao, Jiawei ^{[1
,2
,3
]}

Jia, Yuemeng ^{[5
,6
]}

Mahmut, Dilnar ^{[1
,2
,3
]}

Deik, Amy A. ^{[3
]}

Jeanfavre, Sarah ^{[3
]}

Clish, Clary B. ^{[3
]}

Sankaran, Vijay G. ^{[1
,2
,3
,4
]}

机构：

[1] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[2] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA

[6] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

来源：

CELL | 2023年 / 186卷 / 04期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-SYNTHESIS; ENDOGENOUS ALDEHYDES; CANCER-CELLS; IN-VIVO; ANEMIA; MYSM1; ELTROMBOPAG; METABOLISM; STRESS; DEATH;

D O I：

10.1016/j.cell.2023.01.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet, the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to the loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illustrating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.

引用

页码：732 / 747

页数：16

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