Nguyen, Tra LyNokin, Marie-JulieTerés, SilviaTomé, MercedesBodineau, ClémentGalmar, OrianePasquet, Jean-MaxRousseau, Benoitvan Liempd, SebastianFalcon-Perez, Juan ManuelRichard, ElodieMuzotte, ElodieRezvani, Hamid-RezaPriault, MurielBouchecareilh, MarionRedonnet-Vernhet, IsabelleCalvo, JulienUzan, BenjaminPflumio, FrançoiseFuentes, PatriciaToribio, Maria L.Khatib, Abdel-MajidSoubeyran, PierreMurdoch, Piedad del SocorroDurán, Raúl V.2023-01-122023-01-122020-12-12Nguyen TL, Nokin MJ, Terés S, Tomé M, Bodineau C, Galmar O, et al. Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia. Mol Oncol. 2021 May;15(5):1412-14311574-7891http://hdl.handle.net/10668/4584The 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/GlutamineGlutamine synthetaseMetabolic addictionmTORC1Notch1T-cell acute lymphoblastic leukemiaDownregulationCell lineGlutaminaGlutamato-amoníaco ligasaMetabolismoDiana mecanicista del complejo 1 de la rapamicinaReceptor Notch1Leucemia-linfoma linfoblástico de células T precursorasRegulación hacia abajoLínea celularMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, TumorMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-RegulationMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, EnzymologicMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic::Gene Expression Regulation, LeukemicMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Ligases::Carbon-Nitrogen Ligases::Amide Synthases::Glutamate-Ammonia LigaseMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Basic::GlutamineMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred NODMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, TransgenicMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-LymphomaMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Notch::Receptor, Notch1Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal TransductionMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-RegulationMedical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytesresearch article33314742Acceso abierto10.1002/1878-0261.128771878-0261PMC8096784