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13C mass isotopomer analysis (LCMS flux studies) MLL-AF9 (part I)

ABSTRACT: 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. Research is published: http://www.sciencedirect.com/science/article/pii/S1934590915003744

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Cells

SUBMITTER: Yusuke Saitoh

PROVIDER: ST000308 | MetabolomicsWorkbench | Fri Jun 12 00:00:00 BST 2015

REPOSITORIES: MetabolomicsWorkbench

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13C mass isotopomer analysis (LCMS flux studies) MLL-AF9 (part II)

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