title: Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition.
abstract: Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacque
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Ronchetti
authors.affiliation: Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Clément
authors.initials: C
authors.lastname: Larrue
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Godelieve
authors.initials: G
authors.lastname: Meunier
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Rudy
authors.initials: R
authors.lastname: Birsen
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France; Service d'Hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.affiliation: Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Estelle
authors.initials: E
authors.lastname: Saland
authors.affiliation: INSERM U699, Faculté de Médecine Xavier Bichat, Paris, France; and.
authors.forename: Justine
authors.initials: J
authors.lastname: Decroocq
authors.affiliation: INSERM U699, Faculté de Médecine Xavier Bichat, Paris, France; and.
authors.forename: Thiago Trovati
authors.initials: TT
authors.lastname: Maciel
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Mireille
authors.initials: M
authors.lastname: Lambert
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Laury
authors.initials: L
authors.lastname: Poulain
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Marie Anne
authors.initials: MA
authors.lastname: Hospital
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Sujobert
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France;
authors.forename: Laure
authors.initials: L
authors.lastname: Joseph
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.affiliation: INSERM U699, Faculté de Médecine Xavier Bichat, Paris, France; and.
authors.forename: Ivan Cruz
authors.initials: IC
authors.lastname: Moura
authors.affiliation: Calithera Biosciences, South San Francisco, CA.
authors.forename: Susan
authors.initials: S
authors.lastname: Demo
authors.affiliation: Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Jean Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.affiliation: Cancer Research Center of Toulouse, Unité Mixtes de Recherche 1037 INSERM, Toulouse, France; Université Toulouse III Paul Sabatier, Toulouse, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France; Service d'Hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Tamburini
authors.affiliation: Institut Cochin, Département Développement Reproduction Cancer, Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 8104, INSERM U1016, Paris, France; Ligue National Contre le Cancer, Equipe Labellisée, Paris, France; Service d'Hématologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France;
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D044482:Benzeneacetamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; C000593334:CB-839; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D013830:Thiadiazoles; D005973:Glutamine; C579480:GLS protein, human; D005972:Glutaminase; C579720:venetoclax