安普克
髓系白血病
生物
氧化应激
癌症研究
白血病
AMP活化蛋白激酶
髓样
蛋白激酶A
骨髓
DNA损伤
细胞生物学
激酶
免疫学
内分泌学
生物化学
DNA
作者
Yûsuke Saito,Richard H. Chapple,Angelique Lin,Ayumi Kitano,Daisuke Nakada
出处
期刊:Cell Stem Cell
[Elsevier]
日期:2015-11-01
卷期号:17 (5): 585-596
被引量:198
标识
DOI:10.1016/j.stem.2015.08.019
摘要
How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine acute myeloid leukemia (AML) activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage.
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