ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development
Abstract: Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematologic cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), in which phosphatase and tensin homolog (PTEN) loss defines poor-prognosis patients. We investigated the metabolic rewiring i...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S247395292400658X |
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| author | Guillaume P. Andrieu Guillaume Hypolite Mehdi Latiri Estelle Balducci Caroline Costa Els Verhoeyen Marianne Courgeon Omran Allatif Ivan Nemazanyy Ganna Panasyuk Kathryn Wellen Daniel Herranz Laurent Genestier Elizabeth Macintyre Vahid Asnafi Melania Tesio |
| author_facet | Guillaume P. Andrieu Guillaume Hypolite Mehdi Latiri Estelle Balducci Caroline Costa Els Verhoeyen Marianne Courgeon Omran Allatif Ivan Nemazanyy Ganna Panasyuk Kathryn Wellen Daniel Herranz Laurent Genestier Elizabeth Macintyre Vahid Asnafi Melania Tesio |
| author_sort | Guillaume P. Andrieu |
| collection | DOAJ |
| description | Abstract: Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematologic cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), in which phosphatase and tensin homolog (PTEN) loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming to identify novel metabolic vulnerabilities. We showed that the enzyme adenosine triphosphate (ATP) citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation. Although Pten-mutant mice all died within 17 weeks, the concomitant Acly deletion prevented disease initiation in 70% of the animals. In these animals, ACLY promoted B-cell lymphoma (BCL-2) epigenetic upregulation and prevented the apoptosis of premalignant double-positive thymocytes. Transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells activate ACLY and are sensitive to its genetic targeting. ACLY activation thus represents a metabolic vulnerability with therapeutic potential for high-risk patients with T-ALL. |
| format | Article |
| id | doaj-art-741daebda57c439ea824a8518b9e1109 |
| institution | DOAJ |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-741daebda57c439ea824a8518b9e11092025-08-20T02:54:39ZengElsevierBlood Advances2473-95292025-04-01971670169110.1182/bloodadvances.2024013762ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL developmentGuillaume P. Andrieu0Guillaume Hypolite1Mehdi Latiri2Estelle Balducci3Caroline Costa4Els Verhoeyen5Marianne Courgeon6Omran Allatif7Ivan Nemazanyy8Ganna Panasyuk9Kathryn Wellen10Daniel Herranz11Laurent Genestier12Elizabeth Macintyre13Vahid Asnafi14Melania Tesio15Laboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, FranceLaboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, FranceLaboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, FranceLaboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, FranceVectorology Platform, International Center for Infectiology Research, Institut national de la santé et de la recherche médicale U1111, Lyon, France; Université de Lyon 1, Lyon, France; Centre national de la recherche sciéntifique UMR5308, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, FranceLaboratory of Metabolic control of cellular death, Centre Méditerranéen de Médecine Moléculaire, Institut national de la santé et de la recherche médicale U1065, Nice, FranceLaboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, FrancePlatform Bioinformatics-Biostatistics, Centre International de Recherche en Infectiologie, Institut national de la santé et de la recherche médicale U1111, Lyon, FrancePlatform for Metabolic Analyses, Structure Fédérative de Recherche Necker, Institut national de la santé et de la recherche médicale US24, Paris, France; Centre national de la recherche sciéntifique, unité de recherche associé 3633, Paris, FranceLaboratory of Nutrient Sensing Mechanisms, Institut Necker Enfants Malades, Institut national de la santé et de la recherche médicale U1151, Paris, France; Centre national de la recherche sciéntifique, unité mixte de recherche 8253, Paris, FranceAbramson Family Cancer Research Institute, University of Pennsylvania, Department of Cancer Biology, Perelman School of Medicine, Philadelphia, PARutgers Cancer Institute, Department of Pharmacology, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJUniversité de Lyon 1, Lyon, France; Lymphoma Immune-biology, Centre International de Recherche en Infectiologie, Institut national de la santé et de la recherche médicale U1111, Lyon, France; Centre national de la recherche sciéntifique, unité mixte de recherche 5308, Lyon, FranceLaboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, FranceLaboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Paris, France; Correspondence: Vahid Asnafi, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades, Tour Pasteur, 149 rue de Sèvres, 75015 Paris, France;Laboratory of Onco-Hematology, Institut Necker Enfants Malades, and Institut national de la santé et de la recherche médicale U1115, Paris, France; Université de Lyon 1, Lyon, France; Lymphoma Immune-biology, Centre International de Recherche en Infectiologie, Institut national de la santé et de la recherche médicale U1111, Lyon, France; Centre national de la recherche sciéntifique, unité mixte de recherche 5308, Lyon, France; Melania Tesio, Laboratory Lymphoma-Immune Biology, Facultè de Medicine Lyon-Sud BP-1, 165 Chemin du Grand Revoyet, 69600 Oullins, France;Abstract: Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematologic cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), in which phosphatase and tensin homolog (PTEN) loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming to identify novel metabolic vulnerabilities. We showed that the enzyme adenosine triphosphate (ATP) citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation. Although Pten-mutant mice all died within 17 weeks, the concomitant Acly deletion prevented disease initiation in 70% of the animals. In these animals, ACLY promoted B-cell lymphoma (BCL-2) epigenetic upregulation and prevented the apoptosis of premalignant double-positive thymocytes. Transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells activate ACLY and are sensitive to its genetic targeting. ACLY activation thus represents a metabolic vulnerability with therapeutic potential for high-risk patients with T-ALL.http://www.sciencedirect.com/science/article/pii/S247395292400658X |
| spellingShingle | Guillaume P. Andrieu Guillaume Hypolite Mehdi Latiri Estelle Balducci Caroline Costa Els Verhoeyen Marianne Courgeon Omran Allatif Ivan Nemazanyy Ganna Panasyuk Kathryn Wellen Daniel Herranz Laurent Genestier Elizabeth Macintyre Vahid Asnafi Melania Tesio ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development Blood Advances |
| title | ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development |
| title_full | ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development |
| title_fullStr | ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development |
| title_full_unstemmed | ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development |
| title_short | ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development |
| title_sort | atp citrate lyase is an essential player in the metabolic rewiring induced by pten loss during t all development |
| url | http://www.sciencedirect.com/science/article/pii/S247395292400658X |
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