Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-05-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12877 |
| _version_ | 1819136487678017536 |
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| author | Tra Ly Nguyen Marie‐Julie Nokin Silvia Terés Mercedes Tomé Clément Bodineau Oriane Galmar Jean‐Max Pasquet Benoit Rousseau Sebastian vanLiempd Juan Manuel Falcon‐Perez Elodie Richard Elodie Muzotte Hamid‐Reza Rezvani Muriel Priault Marion Bouchecareilh Isabelle Redonnet‐Vernhet Julien Calvo Benjamin Uzan Françoise Pflumio Patricia Fuentes Maria L. Toribio Abdel‐Majid Khatib Pierre Soubeyran Piedad del Socorro Murdoch Raúl V. Durán |
| author_facet | Tra Ly Nguyen Marie‐Julie Nokin Silvia Terés Mercedes Tomé Clément Bodineau Oriane Galmar Jean‐Max Pasquet Benoit Rousseau Sebastian vanLiempd Juan Manuel Falcon‐Perez Elodie Richard Elodie Muzotte Hamid‐Reza Rezvani Muriel Priault Marion Bouchecareilh Isabelle Redonnet‐Vernhet Julien Calvo Benjamin Uzan Françoise Pflumio Patricia Fuentes Maria L. Toribio Abdel‐Majid Khatib Pierre Soubeyran Piedad del Socorro Murdoch Raúl V. Durán |
| author_sort | Tra Ly Nguyen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T10:35:46Z |
| format | Article |
| id | doaj.art-35c04b323d3d4645a1349eaea077bcd1 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-22T10:35:46Z |
| publishDate | 2021-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-35c04b323d3d4645a1349eaea077bcd12022-12-21T18:29:10ZengWileyMolecular Oncology1574-78911878-02612021-05-011551412143110.1002/1878-0261.12877Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemiaTra Ly Nguyen0Marie‐Julie Nokin1Silvia Terés2Mercedes Tomé3Clément Bodineau4Oriane Galmar5Jean‐Max Pasquet6Benoit Rousseau7Sebastian vanLiempd8Juan Manuel Falcon‐Perez9Elodie Richard10Elodie Muzotte11Hamid‐Reza Rezvani12Muriel Priault13Marion Bouchecareilh14Isabelle Redonnet‐Vernhet15Julien Calvo16Benjamin Uzan17Françoise Pflumio18Patricia Fuentes19Maria L. Toribio20Abdel‐Majid Khatib21Pierre Soubeyran22Piedad del Socorro Murdoch23Raúl V. Durán24Institut Européen de Chimie et Biologie INSERM U1218 Université de Bordeaux Pessac FranceInstitut Européen de Chimie et Biologie INSERM U1218 Université de Bordeaux Pessac FranceInstitut Européen de Chimie et Biologie INSERM U1218 Université de Bordeaux Pessac FranceCentro Andaluz de Biología Molecular y Medicina Regenerativa ‐ CABIMER, Consejo Superior de Investigaciones Científicas Universidad de Sevilla, Universidad Pablo de Olavide Seville SpainInstitut Européen de Chimie et Biologie INSERM U1218 Université de Bordeaux Pessac FranceInstitut Européen de Chimie et Biologie INSERM U1218 Université de Bordeaux Pessac FranceINSERM BMGIC, U1035 University of Bordeaux FranceService Commun des Animaleries University of Bordeaux FranceExosomes Laboratory and Platform of Metabolomics CIC bioGUNECIBERehd Derio SpainExosomes Laboratory and Platform of Metabolomics CIC bioGUNECIBERehd Derio SpainInstitut Bergonié INSERM U1218 University of Bordeaux FranceINSERM BMGIC, U1035 University of Bordeaux FranceINSERM BMGIC, U1035 University of Bordeaux FranceInstitut de Biochimie et Génétique Cellulaires CNRS UMR 5095 Université de Bordeaux FranceBordeaux Research in Translational Oncology INSERM U1053 Université de Bordeaux FranceMaladies Héréditaires du Métabolisme Laboratoire de Biochimie Hôpital Pellegrin CHU Bordeaux FranceUMR967 Inserm CEA Université Paris 7Université Paris 11 Fontenay‐aux‐Roses FranceUMR967 Inserm CEA Université Paris 7Université Paris 11 Fontenay‐aux‐Roses FranceUMR967 Inserm CEA Université Paris 7Université Paris 11 Fontenay‐aux‐Roses FranceCentro de Biología Molecular “Severo Ochoa” Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid SpainCentro de Biología Molecular “Severo Ochoa” Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid SpainAngiogenesis and Cancer Microenvironment Laboratory INSERM U1029 Université de Bordeaux Pessac FranceInstitut Bergonié INSERM U1218 University of Bordeaux FranceCentro Andaluz de Biología Molecular y Medicina Regenerativa ‐ CABIMER, Consejo Superior de Investigaciones Científicas Universidad de Sevilla, Universidad Pablo de Olavide Seville SpainInstitut Européen de Chimie et Biologie INSERM U1218 Université de Bordeaux Pessac FranceThe 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.https://doi.org/10.1002/1878-0261.12877glutamineglutamine synthetasemetabolic addictionmTORC1Notch1T‐cell acute lymphoblastic leukemia |
| spellingShingle | Tra Ly Nguyen Marie‐Julie Nokin Silvia Terés Mercedes Tomé Clément Bodineau Oriane Galmar Jean‐Max Pasquet Benoit Rousseau Sebastian vanLiempd Juan Manuel Falcon‐Perez Elodie Richard Elodie Muzotte Hamid‐Reza Rezvani Muriel Priault Marion Bouchecareilh Isabelle Redonnet‐Vernhet Julien Calvo Benjamin Uzan Françoise Pflumio Patricia Fuentes Maria L. Toribio Abdel‐Majid Khatib Pierre Soubeyran Piedad del Socorro Murdoch Raúl V. Durán Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia Molecular Oncology glutamine glutamine synthetase metabolic addiction mTORC1 Notch1 T‐cell acute lymphoblastic leukemia |
| title | Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia |
| title_full | Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia |
| title_fullStr | Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia |
| title_full_unstemmed | Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia |
| title_short | Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia |
| title_sort | downregulation of glutamine synthetase not glutaminolysis is responsible for glutamine addiction in notch1 driven acute lymphoblastic leukemia |
| topic | glutamine glutamine synthetase metabolic addiction mTORC1 Notch1 T‐cell acute lymphoblastic leukemia |
| url | https://doi.org/10.1002/1878-0261.12877 |
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