title: Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia.
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.
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sujobert
authors.affiliation: 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.
authors.forename: Laury
authors.initials: L
authors.lastname: Poulain
authors.affiliation: 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.
authors.forename: Etienne
authors.initials: E
authors.lastname: Paubelle
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Zylbersztejn
authors.affiliation: 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.
authors.forename: Adrien
authors.initials: A
authors.lastname: Grenier
authors.affiliation: 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.
authors.forename: Mireille
authors.initials: M
authors.lastname: Lambert
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Townsend
authors.affiliation: GlaxoSmithKline Research Center, 91490 Les Ulis, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Brusq
authors.affiliation: GlaxoSmithKline Research Center, 91490 Les Ulis, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
authors.affiliation: 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.
authors.forename: Justine
authors.initials: J
authors.lastname: Decrooqc
authors.affiliation: Division for Hematology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway.
authors.forename: Ina
authors.initials: I
authors.lastname: Nepstad
authors.affiliation: 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.
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.affiliation: 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.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mondesir
authors.affiliation: 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.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Hospital
authors.affiliation: 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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacque
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Christodoulou
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Desouza
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: 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.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: 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.
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.affiliation: 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.
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
authors.affiliation: 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.
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D046912:Multiprotein Complexes / Q000819:agonists*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011744:Pyrimidinones / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
chemical_list: D000970:Antineoplastic Agents; C000606536:GSK621; D007093:Imidazoles; D046912:Multiprotein Complexes; D011744:Pyrimidinones; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases