title: AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Chapple
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Lin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kitano
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: nakada@bcm.edu.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakada
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D055372:AMP-Activated Protein Kinases
keywords: AML; AMPK; DNA damage; ROS; dietary restriction; glycolysis; leukemia-initiating cells; metabolic stress