1. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia
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Clément Bodineau, Benjamin Uzan, Sebastian van Liempd, Jean-Max Pasquet, Juan M. Falcón-Pérez, Elodie Muzotte, H. Rezvani, Julien Calvo, Elodie Richard, María L. Toribio, Patricia Fuentes, Isabelle Redonnet-Vernhet, Silvia Terés, Marion Bouchecareilh, Mercedes Tomé, Pierre Soubeyran, Piedad del Socorro Murdoch, Benoit Rousseau, Tra Ly Nguyen, Françoise Pflumio, Marie-Julie Nokin, Oriane Galmar, Raúl V. Durán, Abdel-Majid Khatib, Muriel Priault, Centre National de la Recherche Scientifique (CNRS), Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Ministerio de Ciencia, Innovación y Universidades (MICINN). España, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Agencia Estatal de Investigación (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Institut National de la Santé et de la Recherche Médicale (France), Ligue Nationale contre le Cancer (France), Université de Bordeaux, Fondation pour la Recherche Médicale, Conseil régional d'Aquitaine, Fondation ARC pour la Recherche sur le Cancer, Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), [Nguyen,TL, Nokin,MJ, Terés,S, Bodineau,C, Galmnar,O, Durán,RV] Institut Europeen de Chimie et Biologie, INSERM U1218, Université de Bordeaux, Pessac, France. [Tomé,M, Murdoch,PDS, Durán,RV] Centro Andaluz de Biología Molecular y Medicina Regenerativa - CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Seville, Spain. [Tomé,M, Khatib,AM] Angiogenesis and Cancer Microenvironment Laboratory INSERM U1029, Universite de Bordeaux, Pessac, France. [Pasquet,JM, Muzotte,E, Rezvani,HR] INSERM, BMGIC, U1035, University of Bordeaux, France. [Rousseau,B] Service Commun des Animaleries, University of Bordeaux, France. [van Liempd,S, Falcon-Perez,JM] Exosomes Laboratory and Platform of Metabolomics, CIC bioGUNE, CIBERehd, Derio, Spain. [Falcon-Perez,JM] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. [Richard,E] Institut Bergonie, INSERM U1218, University of Bordeaux, France. [Priault,M] Institut de Biochimie et Gen etique Cellulaires, CNRS UMR 5095, Université de Bordeaux, France. [Bouchecareilh,M] Bordeaux Research in Translational Oncology, INSERM U1053, Universite de Bordeaux, France. [Redonnet-Vernhet,I] Maladies Heréditaires du Métabolisme, Laboratoire de Biochimie, Hôpital Pellegrin, CHU Bordeaux, France. [Calvo,J, Uzan,B, Pflumio, F] UMR967, Inserm, CEA, Universite Paris 7, UniversitéParis 11, Fontenay-aux-Roses, France. [Fuentes,P, Toribio,ML] Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid, Spain. [Murdoch,PDS] Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Spain, and This work was supported by funds from the following institutions: Agencia Estatal de Investigación/European Regional Development Fund, European Union (PGC2018-096244-B-I00, SAF2016-75442-R), Ministry of Science, Innovation and Universities of Spain, Spanish National Research Council—CSIC, Institut National de la Santé et de la Recherche Médicale—INSERM, Ligue Contre le Cancer—Gironde, Université de Bordeaux, Fondation pour la Recherche Médicale, the Conseil Régional d'Aquitaine, SIRIC-BRIO, Fondation ARC and Institut Européen de Chimie et Biologie. MJN was supported by a bourse d’excellence de la Fédération Wallonie-Bruxelles (WBI) and a postdoctoral fellowship from Fondation ARC. We thank Vincent Pitard (Flow Cytometry Platform, Université de Bordeaux, France) for technical assistance in flow cytometry experiments. We thank Diana Cabrera (Metabolomics Platform, CIC bioGUNE, Spain) for technical assistance in metabolomics analysis.
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0301 basic medicine ,Male ,Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings] ,Cancer Research ,Glutamina ,Regulación hacia abajo ,[SDV]Life Sciences [q-bio] ,Glutamine ,mTORC1 ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Diana mecanicista del complejo 1 de la rapamicina ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Receptor, Notch1 ,Research Articles ,RC254-282 ,ComputingMilieux_MISCELLANEOUS ,Metabolismo ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred NOD [Medical Subject Headings] ,Chemistry ,Gene Expression Regulation, Leukemic ,Línea celular ,Metabolicaddiction ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings] ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,3. Good health ,Leukemia ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,cardiovascular system ,Molecular Medicine ,biological phenomena, cell phenomena, and immunity ,Glutamato-amoníaco ligasa ,T-cell acute lymphoblastic leukemia ,Research Article ,Signal Transduction ,Receptor Notch1 ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Notch::Receptor, Notch1 [Medical Subject Headings] ,Down-Regulation ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic::Gene Expression Regulation, Leukemic [Medical Subject Headings] ,Check Tags::Male [Medical Subject Headings] ,Mice, Transgenic ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mechanistic Target of Rapamycin Complex 1 ,Gene Expression Regulation, Enzymologic ,Glutamine synthetase ,03 medical and health sciences ,Downregulation and upregulation ,Glutamate-Ammonia Ligase ,Cell Line, Tumor ,T‐cell acute lymphoblastic leukemia ,Diseases::Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma [Medical Subject Headings] ,Genetics ,medicine ,Animals ,Humans ,Metabolic addiction ,T-cell acutelymphoblastic leukemia ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Notch1 ,Glutaminolysis ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation [Medical Subject Headings] ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-Regulation [Medical Subject Headings] ,Cell growth ,Leucemia-linfoma linfoblástico de células T precursoras ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Basic::Glutamine [Medical Subject Headings] ,medicine.disease ,Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Carbon-Nitrogen Ligases::Amide Synthases::Glutamate-Ammonia Ligase [Medical Subject Headings] ,Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Enzymologic [Medical Subject Headings] ,030104 developmental biology ,Apoptosis ,Downregulation ,metabolic addiction ,Cancer research ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Transgenic [Medical Subject Headings] ,sense organs ,Cell line - Abstract
During glutamine sufficiency, both Notch‐positive and Notch‐negative T‐ALL cells promote glutamine catabolism, leading to mammalian target of rapamycin complex 1 (mTORC1) activation and cell growth and proliferation. However, during glutamine scarcity, only Notch‐negative T‐ALL cells can perform a metabolic adaptation by promoting glutamine synthesis. By contrast, Notch‐positive T‐ALL cells maintain glutamine catabolism during glutamine restriction, leading to glutamine addiction and mTORC1 dependency., The cellular receptor Notch1 is a central regulator of T‐cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T‐cell acute lymphoblastic leukemia (T‐ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T‐ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti‐Notch therapies in T‐ALL models. In this work, we report that Notch1 upregulation in T‐ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1‐driven T‐ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1‐induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1‐driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1‐driven leukemia.
- Published
- 2021