2. Academic Validation
  3. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

  • Cell Rep. 2015 Jun 9;11(9):1446-57. doi: 10.1016/j.celrep.2015.04.063.
Pierre Sujobert 1,  Laury Poulain 1,  Etienne Paubelle 2,  Florence Zylbersztejn 2,  Adrien Grenier 1,  Mireille Lambert 1,  Elizabeth C Townsend 3,  Jean-Marie Brusq 4,  Edwige Nicodeme 4,  Justine Decrooqc 2,  Ina Nepstad 5,  Alexa S Green 1,  Johanna Mondesir 1,  Marie-Anne Hospital 1,  Nathalie Jacque 1,  Alexandra Christodoulou 3,  Tiffany A Desouza 3,  Olivier Hermine 2,  Marc Foretz 6,  Benoit Viollet 6,  Catherine Lacombe 1,  Patrick Mayeux 1,  David M Weinstock 3,  Ivan C Moura 2,  Didier Bouscary 1,  Jerome Tamburini 7
Affiliations

Affiliations

  • 1 INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR8104, 75014 Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, 75005 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), 75013 Paris, France.
  • 2 INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, 75015 Paris, France; Laboratory of Excellence GR-Ex, 75015 Paris, France.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • 4 GlaxoSmithKline Research Center, 91490 Les Ulis, France.
  • 5 Division for Hematology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.
  • 6 INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR8104, 75014 Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, 75005 Paris, France; Laboratory of Excellence GR-Ex, 75015 Paris, France.
  • 7 INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR8104, 75014 Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, 75005 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), 75013 Paris, France. Electronic address: jerome.tamburini@inserm.fr.
PMID: 26004183 DOI: 10.1016/j.celrep.2015.04.063
Abstract

AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of Akt or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.

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