干细胞
半胱氨酸
白血病
化学
癌症研究
细胞生物学
生物
生物化学
遗传学
酶
作者
Courtney L. Jones,Brett M. Stevens,Angelo D’Alessandro,Rachel Culp‐Hill,Julie A. Reisz,Shanshan Pei,Annika Gustafson,Nabilah Khan,James DeGregori,Daniel A. Pollyea,Craig T. Jordan
出处
期刊:Blood
[Elsevier BV]
日期:2019-05-17
卷期号:134 (4): 389-394
被引量:151
标识
DOI:10.1182/blood.2019898114
摘要
Abstract We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.
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