ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development

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.

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Publication Details

Journal
Blood Advances
Published
2024-11-15
DOI
https://doi.org/10.1182/bloodadvances.2024013762
Citations
2
Primary Topic
Cholangiocarcinoma and Gallbladder Cancer Studies
Type
article
Field-Weighted Citation Impact
1.15

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article

ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development

Els Verhoeyen, Melania Tesio, Mehdi Latiri, Ivan Nemazanyy et al.
2 citations
Blood Advances
Cholangiocarcinoma and Gallbladder Cancer Studies
1.15
article

ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development

Els Verhoeyen, Melania Tesio, Mehdi Latiri, Ivan Nemazanyy, Guillaume Hypolite, Guillaume P. Andrieu, Estelle Balducci, Omran Allatif, Elizabeth Macintyre, Ganna Panasyuk, Laurent Genestier, Daniel Herranz, Kathryn E. Wellen, Vahid Asnafi, Caroline Costa, Marianne Courgeon
article en
2 citations

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.

Blood AdvancesVol. 9(7)
Université Claude Bernard Lyon 1 (FR), Rutgers, The State University of New Jersey (US), École Normale Supérieure de Lyon (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Cancer Research Institute (US), Université Paris Cité (FR), Agence Nationale de la Recherche (FR), Johnson University (US), Institut Necker Enfants Malades (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre Méditerranéen de Médecine Moléculaire (FR), Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition (FR), Cancer Research Center (US), UPMC Hillman Cancer Center (US), Institut des Maladies Métaboliques et Cardiovasculaires (FR), Laboratoire Interuniversitaire de Biologie de la Motricité (FR), Centre International de Recherche en Infectiologie (FR), Institut Français de l'Éducation (FR), Structure fédérative de recherche Necker (FR)
Fondation de France
No poverty
Openalex Percentile: Top 19%
Cholangiocarcinoma and Gallbladder Cancer Studies
1.15
DOIOpen Access PDFOpenAlex
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