AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.

Mon, 2016-01-25 10:58 -- voskuhlt
TitleAMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow.
Publication TypeJournal Article
Year of Publication2015
AuthorsSaito Y, Chapple RH, Lin A, Kitano A, Nakada D
JournalCell Stem Cell
Volume17
Issue5
Pagination585-96
Date Published2015 Nov 5
ISSN1875-9777
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.

DOI10.1016/j.stem.2015.08.019
Alternate JournalCell Stem Cell
PubMed ID26440282
PubMed Central IDPMC4597792
Grant ListR01 CA193235 / CA / NCI NIH HHS / United States