Author: "Claudie Bosc" - Searchworks@Jio Institute Digital Library Search Results

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1. Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

Author: Clément Larrue, Nathan Guiraud, Pierre-Luc Mouchel, Marine Dubois, Thomas Farge, Mathilde Gotanègre, Claudie Bosc, Estelle Saland, Marie-Laure Nicolau-Travers, Marie Sabatier, Nizar Serhan, Ambrine Sahal, Emeline Boet, Sarah Mouche, Quentin Heydt, Nesrine Aroua, Lucille Stuani, Tony Kaoma, Linus Angenendt, Jan-Henrik Mikesch, Christoph Schliemann, François Vergez, Jérôme Tamburini, Christian Récher, and Jean-Emmanuel Sarry
Subjects: Science
Abstract: Leukemic stem cells which are resistant to chemotherapy are proposed as relapse-initiating cells (RICs). Here, the authors show that targeting the adrenomedullin-calcitonin receptor-like receptor decreases RICs frequency improving chemotherapy response in AML preclinical models.
Published: 2021
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2. Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites

Author: Claudie Bosc, Nicolas Broin, Marjorie Fanjul, Estelle Saland, Thomas Farge, Charly Courdy, Aurélie Batut, Rawand Masoud, Clément Larrue, Sarah Skuli, Nicolas Espagnolle, Jean-Christophe Pagès, Alice Carrier, Frédéric Bost, Justine Bertrand-Michel, Jérôme Tamburini, Christian Récher, Sarah Bertoli, Véronique Mansat-De Mas, Stéphane Manenti, Jean-Emmanuel Sarry, and Carine Joffre
Subjects: Science
Abstract: How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML.
Published: 2020
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3. FAO-supported OxPhos leukemic stem cells are sensitive to cold

Author: Emmanuel Griessinger, Diego Pereira-Martins, Marielle Nebout, Claudie Bosc, Estelle Saland, Emilie Boet, Ambrine Sahal, Johanna Chiche, Delphine Debayle, Lucille Fleuriot, Maurien Pruis, Véronique De Mas, François Vergez, Christian Récher, Gerwin Huls, Jean-Emmanuel Sarry, Jan Jacob Schuringa, and Jean-François Peyron
Abstract: Targeting mitochondrial oxidative phosphorylation (OxPhos) metabolism has revealed a potential weakness for leukemic stem cells (LSCs) that can be exploited for therapeutic purposes. Fatty acids oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some AML and for chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge: CKC4), as a novel vulnerability that selectively kills FAO-supported OxPhos LSCs in Acute Myeloid Leukemia while sparing normal hematopoietic stem cells (HSCs). Cell death of OxPhos leukemic cells was induced by membrane permeabilization at 4°C while by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells into OxPhos metabolism sensitized them to CKC4. We show using lipidomic and proteomic analyzes that OxPhos shapes the composition of the plasma membrane and introduce variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Cold sensitivity is a potential OxPhos biomarker.SignificanceThis study reveals that mitochondrial energetics fueled by FAO metabolism introduces membrane fragility upon cold exposure in OxPhos-driven AMLs and in LSCs. This novel physical property of Leukemic cells and LSCs opens new avenues for biomarker and diagnostics as well as for anti-OxPhos drug screening and LSCs targeting.One Sentence SummaryOxPhos leukemic cells die at 4°C
Published: 2023
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4. Supplementary Table S4 from Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

Author: Jean-Emmanuel Sarry, François Vergez, Christian Récher, Jérome Tamburini, Carine Joffre, Tony Kaoma, Francisco Azuaje, Nathalie Nicot, Jean-Charles Portais, Floriant Bellvert, Nathalie Bonnefoy, Mathilde Gotanègre, Camille Laurent, Charlotte Syrykh, Muriel Picard, Massimiliano Bardotti, Sarah Gandarillas, Latifa Jarrou, Clément Larrue, Fetta Mazed, Marie Sabatier, Lucille Stuani, Claudie Bosc, Thomas Farge, Pierre-Luc Mouchel, Mohsen Hosseini, Fabienne de Toni, Ryan Gwilliam, Estelle Saland, Marie-Laure Nicolau-Travers, Margherita Ghisi, Emeline Boet, and Nesrine Aroua
Abstract: Table S4
Published: 2023
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5. Supplementary Table S6 from Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

Author: Jean-Emmanuel Sarry, Christian Récher, Martin Carroll, Gwenn Danet-Desnoyers, Mary Selak, François Vergez, Jean-Charles Portais, Barbara H. Garmy-Susini, François Delhommeau, Lara Gales, Tony Palama, Pierre Hirsch, Yara Barreira, Olivier Duchamp, Yves Collette, Emmanuel Griessinger, Rémy Castellano, Camille Montersino, Laetitia K. Linares, Jason Iacovoni, Laurent Vallar, Tony Kaoma, Suzanne Tavitian, Audrey Sarry, Nizar Serhan, Marion David, Nicolas Broin, Stéphanie Cassant-Sourdy, Marie-Laure Nicolau-Travers, Virginie Féliu, Héléna Boutzen, Clément Larrue, Sarah Scotland, Marine Fraisse, Lucille Stuani, Mayumi Sugita, Claudie Bosc, Robin Perry, Mohsen Hosseini, Nesrine Aroua, Fabienne de Toni, Estelle Saland, and Thomas Farge
Abstract: HIGH CD36 gene signature generated from upregulated genes in AML patients that express the most CD36 mRNA compared to that of the lowest expression of CD36 in TCGA cohort.
Published: 2023
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6. Supplementary Methods and Supplementary Figures 1 through 18 from Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

Author: Jean-Emmanuel Sarry, Christian Récher, Martin Carroll, Gwenn Danet-Desnoyers, Mary Selak, François Vergez, Jean-Charles Portais, Barbara H. Garmy-Susini, François Delhommeau, Lara Gales, Tony Palama, Pierre Hirsch, Yara Barreira, Olivier Duchamp, Yves Collette, Emmanuel Griessinger, Rémy Castellano, Camille Montersino, Laetitia K. Linares, Jason Iacovoni, Laurent Vallar, Tony Kaoma, Suzanne Tavitian, Audrey Sarry, Nizar Serhan, Marion David, Nicolas Broin, Stéphanie Cassant-Sourdy, Marie-Laure Nicolau-Travers, Virginie Féliu, Héléna Boutzen, Clément Larrue, Sarah Scotland, Marine Fraisse, Lucille Stuani, Mayumi Sugita, Claudie Bosc, Robin Perry, Mohsen Hosseini, Nesrine Aroua, Fabienne de Toni, Estelle Saland, and Thomas Farge
Abstract: Supplementary Methods. Supplementary Figure S1. Clinical distributions of AML patients from TUH and 3 independent patient cohorts. Supplementary Figure S2. In vivo treatment with 60 mg/kg/d of cytarabine (AraC) given daily for 5 days induces a significant reduction of the total cell tumor burden in AML-engrafted mice. Supplementary Figure S3. In vivo cytarabine (AraC) treatment induces significant but heterogeneous response in bone marrow and spleen of AML-xenografted NSG mice. Supplementary Figure S4. Comparative analysis of the in vivo response to cytarabine (AraC) with clinicobiological data of AML patients. Supplementary Figure S5. In vivo cytarabine (AraC) treatment induces changes in CD34+/-CD38+/- phenotypes in AML-engrafted mice. Supplementary Figure S6. In vivo cytarabine (AraC) chemotherapy treatment leads to reduction of the absolute number of human CD34+CD38+/- populations in AML. Supplementary figure S7. No enrichment in G0 quiescent cells was observed in mice treated with sublethal dose of cytarabine (AraC) for 5 days in vivo. Supplementary figure S8. Mitochondrial and energetic features of LOW (KG1, KG1a, U937) and HIGH (MOLM14, MV4-11, HL60) OXPHOS AML cell lines. Supplementary figure S9. Functional analysis of the transcriptomes of LOW (KG1a, U937) versus HIGH (MOLM14, HL60) OXPHOS AML cell lines untreated or treated with metformin. Supplementary figure S10. AML cells surviving after cytarabine (AraC) treatment are resistant to chemotherapies and are pre-existing CD36+CD44+ phenotype with an increased oxidative metabolism. Supplementary figure S11. Culture in galactose induces energetic shift of LOW OXPHOS AML U937 cells toward HIGH OXPHOS state, leading to cytarabine (AraC) resistance in AML. Supplementary figure S12. Energetic shift of mtDNA-depleted Rho0 MOLM14 cells toward LOW OXPHOS state induces AraC sensitivity. Supplementary figure S13. Electron Transfer Chain Complex I inhibition by Phenformin (Phenf) induces energetic shift toward LOW OXPHOS state and increases cytarabine (AraC) sensitivity in MOLM14 cells. Supplementary figure S14. Electron Transfer Chain Complex I inhibition by Metformin (Met) induces energetic shift toward LOW OXPHOS state and increases cytarabine (AraC) sensitivity in MOLM14 cells. Supplementary figure S15. Electron Transfer Chain Complex I inhibition by Rotenone (Rot) induces energetic shift toward LOW OXPHOS state and increases cytarabine (AraC) sensitivity in MOLM14 cells. Supplementary figure S16. Electron Transfer Chain Complex III inhibition by Antimycin A (AntiA) induces energetic shift toward LOW OXPHOS state and increases cytarabine (AraC) sensitivity in MOLM14 cells. Supplementary figure S17. Electron Transfer Chain Complex III inhibition by Atovaquone (ATQ) induces energetic shift toward LOW OXPHOS state and increases cytarabine (AraC) sensitivity in MOLM14 cells. Supplementary figure S18. Working model of the resistance to AraC in vivo.
Published: 2023
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7. Supplementary Data from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author: Jean-Emmanuel Sarry, Christian Récher, Guillaume Bossis, Marc Piechaczyk, Mathilde Gotanègre, Pierre Luc Mouchel, Marie Sabatier, Clément Larrue, Latifa Jarrou, Sonia Zaghdoudi, Véronique Guyonnet-Dupérat, Estelle Saland, Thomas Farge, Claudie Bosc, Nesrine Aroua, Hamid Reza Rezvani, and Mohsen Hosseini
Abstract: Supplementary Table 1 Clinical and mutational features of AML patient samples used in this study
Published: 2023
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8. Supplementary Figures from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author: Jean-Emmanuel Sarry, Christian Récher, Guillaume Bossis, Marc Piechaczyk, Mathilde Gotanègre, Pierre Luc Mouchel, Marie Sabatier, Clément Larrue, Latifa Jarrou, Sonia Zaghdoudi, Véronique Guyonnet-Dupérat, Estelle Saland, Thomas Farge, Claudie Bosc, Nesrine Aroua, Hamid Reza Rezvani, and Mohsen Hosseini
Abstract: Supplementary Figures 1-7
Published: 2023
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9. Supplementary Methods from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author: Jean-Emmanuel Sarry, Christian Récher, Guillaume Bossis, Marc Piechaczyk, Mathilde Gotanègre, Pierre Luc Mouchel, Marie Sabatier, Clément Larrue, Latifa Jarrou, Sonia Zaghdoudi, Véronique Guyonnet-Dupérat, Estelle Saland, Thomas Farge, Claudie Bosc, Nesrine Aroua, Hamid Reza Rezvani, and Mohsen Hosseini
Abstract: Supplementary Methods
Published: 2023
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10. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia

Author: Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloe Friedrich, Anne-Sophie Alary, Helene Guermouche, Ambrine Sahal, Guillemette Fouquet, Mathilde Gotanègre, Federico Simonetta, Sarah Mouche, Pierre Gestraud, Auriane Lescure, Elaine Del Nery, Claudie Bosc, Adrien Grenier, Fetta Mazed, Johanna Mondesir, Nicolas Chapuis, Liza Ho, Aicha Boughalem, Marc Lelorc’h, Camille Gobeaux, Michaela Fontenay, Christian Recher, Norbert Vey, Arnaud Guillé, Daniel Birnbaum, Olivier Hermine, Isabelle Radford-Weiss, Petros Tsantoulis, Yves Collette, Rémy Castellano, Jean-Emmanuel Sarry, Eric Pasmant, Didier Bouscary, Olivier Kosmider, Jerome Tamburini, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Cité (UPCité), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Sud Francilien, Laboratorio d'Informatica Musicale (LIM), Università degli Studi di Milano = University of Milan (UNIMI), Institut Curie [Paris], Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Translational Research Department, Institut Curie, BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Université de Genève = University of Geneva (UNIGE), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Laboratoire CERBA [Saint Ouen l'Aumône], Département d’Oncologie Médicale [IPC, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Mitogen-Activated Protein Kinase Kinases, Cancer Research, [SDV]Life Sciences [q-bio], Hematology, Proto-Oncogene Proteins p21(ras), Leukemia, Myeloid, Acute, Mice, Oxidative Stress, fms-Like Tyrosine Kinase 3, Oncology, hemic and lymphatic diseases, Mutation, Animals, Humans, Synthetic Lethal Mutations, neoplasms
Abstract: Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML.
Published: 2022
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11. In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

Author: Guillaume Cognet, Lucille Stuani, Thomas Farge, Mathilde Gotanègre, Maud Heuillet, Lara Gales, Amandine Rocher, Nina Lager-Lachaud, Claudie Bosc, Marie Sabatier, Estelle Saland, Ambrine Sahal, Laura Poillet-Perez, Francois Vergez, Véronique de Mas, Christian Récher, Jean-Charles Portais, Floriant Bellvert, Jean-Emmanuel Sarry, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: in vivo metabolomics, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, leukemia, prediction, metabolic niche, OxPHOS state
Abstract: Background Metabolic adaptation is a hallmark of cancer including acute myeloid leukemia (AML). Tumor microenvironment is also described as an essential support of leukemic metabolism. We explored how systemic and tissue metabolism was rewired in leukemia-bearing mice and upon chemotherapy. Methods Using AML cell line- and primary patient-derived xenograft models, we developed in vivo metabolomics to uncover the metabolic pattern of 10 tissues including plasma, bone marrow, spleen, liver, adipose tissue, lung, pancreas, kidney, heart and muscle. Results In vivo targeted mass spectrometry allowed metabolic characterization of tissues from naïve and AML-xenografted immunocompromised mice. AML xenotransplantation and cytarabine treatment induced AML cell type-dependent global changes in tissue metabolomes. Infiltration of high OxPHOS MOLM14 cells that are intrinsically chemoresistant, induced minor changes in tissue metabolomes. In contrast, low OxPHOS U937 xenograft led to major reprogramming of metabolic tissue niches for survival upon chemotherapy. Interestingly, plasma metabolite signatures could predict the oxidative phenotype of leukemic cells. Conclusion Major metabolic changes in host tissues play a crucial role in tumor xenotransplantation and define their OxPHOS state in AML. Since mitochondrial phenotype is an essential determinant of drug response in AML, plasma metabolite signatures might be novel biomarkers for patient stratification.
Published: 2022

12. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia

Author: Jean-Emmanuel Sarry, Thomas Farge, Eléonore Kaphan, Emeline Boet, Francois Vergez, Marie Sabatier, Jérôme Kluza, Nathalie Nicot, Yujue Wang, Andrew H. Wei, Aurélie Bousard, Noémie Gadaud, Pierre-Luc Mouchel, Ambrine Sahal, Nesrine Aroua, Ing Soo Tiong, Nathaniel Polley, Lucille Stuani, Mathilde Gotanègre, Quentin Fovez, Tony Kaoma, Laura Poillet-Perez, Claudie Bosc, Estelle Saland, Marie Tosolini, Guillaume Cognet, Rafael J. Argüello, Florian Rambow, Jean-Jacques Fournié, Christian Recher, Carine Joffre, Clément Larrue, Xiaoyang Su, Jean-Christophe Marine, Jerome Tamburini, Céline Mazzotti, Muriel Picard, Hervé Avet-Loiseau, Florence Cabon, Latifa Jarrou, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), LabEx Toucan, LabEx Toucan - Toulouse, Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Université Toulouse III Paul Sabatier - Faculté de médecine Purpan (UTPS), Université de Toulouse (UT)-Université de Toulouse (UT), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Anesthésie Réanimation [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Luxembourg Institute of Health (LIH), Rutgers cancer institute of New Jersey [Newark, NJ], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), and The Alfred Hospital and Monash University - Department of Clinical Haematology - Melbourne
Subjects: Cancer Research, Combination therapy, [SDV]Life Sciences [q-bio], Cell, Oxidative phosphorylation, chemistry.chemical_compound, In vivo, hemic and lymphatic diseases, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, Sulfonamides, business.industry, Venetoclax, Cytarabine, Myeloid leukemia, Pyruvate dehydrogenase complex, Bridged Bicyclo Compounds, Heterocyclic, carbohydrates (lipids), Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, chemistry, Cancer research, Azacitidine, business, medicine.drug
Abstract: Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a ‘MitoScore’ signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies. Sarry and colleagues demonstrate that adaptive resistance to venetoclax + cytarabine therapy in acute myeloid leukemia relies on mitochondrial respiration and show that combination with electron transport chain complex inhibitors delays relapse in patient-derived xenograft models in vivo.
Published: 2021
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13. AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia

Author: Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal, Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed, Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick Auberger, Andrew A. Lane, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, and Jerome Tamburini
Subjects: Adult, Male, Adolescent, THP-1 Cells, Citric Acid Cycle, Drug Evaluation, Preclinical, Antineoplastic Agents, Apoptosis, HL-60 Cells, Pyrimidinones, AMP-Activated Protein Kinases, General Biochemistry, Genetics and Molecular Biology, Oxidative Phosphorylation, Mice, Young Adult, eIF-2 Kinase, Cell Line, Tumor, Animals, Humans, Aged, Aged, 80 and over, Sulfonamides, Imidazoles, U937 Cells, Middle Aged, Bridged Bicyclo Compounds, Heterocyclic, Mitochondria, Leukemia, Myeloid, Acute, HEK293 Cells, Proto-Oncogene Proteins c-bcl-2, Unfolded Protein Response, Female
Abstract: AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.
Published: 2021

14. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia

Author: Lara Gales, Camille Montersino, Marc Conti, Pierre Bories, Courtney D. DiNardo, Brandon Nicolay, Fabien Jourdan, Nicolas Broin, Mohsen Hosseini, Guillaume Cognet, Yves Gibon, Marie Sabatier, Tony Kaoma, Marina Konopleva, Lucille Stuani, Mathilde Gotanègre, Christian Recher, Laurent Fernando, Vera Pancaldi, Nathalie Poupin, Estelle Saland, Jean-Emmanuel Sarry, Joseph R. Marszalek, Andrei Turtoi, Thomas Farge, Feng Wang, Yves Collette, Laurent Le Cam, Madi Y. Cissé, Cédric Cassan, Alexis Hucteau, Claudie Bosc, Natalia Baran, Sebastien Ronseaux, Aliki Zavoriti, François Fenaille, Florence Castelli, Laetitia K. Linares, Evgenia Turtoi, Emeline Chu-Van, Martin Carroll, Pierre-Luc Mouchel, Mary A. Selak, Guillaume Cazals, Emeline Boet, Rémy Castellano, Floriant Bellvert, Norbert Vey, Clément Larrue, Koichi Takahashi, Ambrine Sahal, Sylvain Loric, Jean-Charles Portais, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Métabolisme et Xénobiotiques (ToxAlim-MeX), ToxAlim (ToxAlim), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Institute of Health (LIH), Biologie du fruit et pathologie (BFP), Université de Bordeaux (UB)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pennsylvania, Université de Montpellier (UM), Réseau régional de cancérologie Onco-Occitanie, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agios Pharmaceuticals, ANR-11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), ANR-11-LABX-0068,TOUCAN,Analyse intégrée de la résistance dans les cancers hématologiques(2011), ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Laboratoire de Mesures Physiques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), STROMALab, Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), collette, yves, Pôle hospitalier Universitaire Cancer (PHUC) - Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région - - CAPTOR2011 - ANR-11-PHUC-0001 - PHUC - VALID, Analyse intégrée de la résistance dans les cancers hématologiques - - TOUCAN2011 - ANR-11-LABX-0068 - LABX - VALID, and Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation - - METABOHUB2011 - ANR-11-INBS-0010 - INBS - VALID
Subjects: Pyridines, [SDV]Life Sciences [q-bio], Mutant, Aminopyridines, Mice, SCID, Mitochondrion, medicine.disease_cause, Oxidative Phosphorylation, Epigenesis, Genetic, 0302 clinical medicine, Piperidines, Mice, Inbred NOD, hemic and lymphatic diseases, Immunology and Allergy, Enzyme Inhibitors, Mice, Knockout, 0303 health sciences, Mutation, Oxadiazoles, Chemistry, Triazines, Myeloid leukemia, Isocitrate Dehydrogenase, 3. Good health, Mitochondria, [SDV] Life Sciences [q-bio], Isoenzymes, Leukemia, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Doxycycline, Acute Disease, Immunology, Glycine, HL-60 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Epigenetics, Protein kinase B, 030304 developmental biology, medicine.disease, Xenograft Model Antitumor Assays, Leukemia & Lymphoma, Metabolism, Drug Resistance, Neoplasm, Cancer cell, Cancer research
Abstract: Stuani et al. demonstrate that IDH mutant AML cells display an enhanced mitochondrial phenotype, which is not reversed by IDH mutant inhibitors. This study provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors., Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors., Graphical Abstract
Published: 2021
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15. Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

Author: Margherita Ghisi, Jerome Tamburini, Marie Sabatier, Massimiliano Bardotti, Francisco Azuaje, Jean-Charles Portais, Christian Récher, Carine Joffre, Lucille Stuani, Pierre-Luc Mouchel, Camille Laurent, Marie-Laure Nicolau-Travers, Fetta Mazed, Claudie Bosc, Nathalie Nicot, Nesrine Aroua, Mathilde Gotanègre, Jean-Emmanuel Sarry, Estelle Saland, Clément Larrue, Floriant Bellvert, Fabienne De Toni, Latifa Jarrou, Mohsen Hosseini, Charlotte Syrykh, Ryan Gwilliam, François Vergez, Tony Kaoma, Sarah Gandarillas, Muriel Picard, Thomas Farge, Emeline Boet, Nathalie Bonnefoy, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Genève = University of Geneva (UNIGE), Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Anesthésie Réanimation [CHU de Toulouse], Service d'anatomopathologie, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Luxembourg Institute of Health (LIH), Canceropole GSO 2014-E07, Région Auvergne-Rhone-AlpesRégion Bourgogne-Franche-ComteRégion Hauts-de-FranceRégion Nouvelle-Aquitaine, Fondation Toulouse Cancer Santé, Plan Cancer 2014-BioSys, Fondation ARC, Fondation de France, ANR-11-LABX-0068,TOUCAN,Analyse intégrée de la résistance dans les cancers hématologiques(2011), ANR-11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Genève (UNIGE), Intensive Care Unit, Department of Anesthesiology and Critical Care, Rangueil Hospital, Centre Hospitalier Universitaire, Toulouse, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: 0301 basic medicine, Male, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, In vivo, Antigens, CD, hemic and lymphatic diseases, medicine, Humans, Ectonucleotidase, Cytotoxicity, business.industry, Apyrase, Cytarabine, Myeloid leukemia, Middle Aged, 3. Good health, Mitochondria, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Oncology, Cell culture, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Female, business, medicine.drug
Abstract: Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell-surface expression and activity is increased in patients with AML upon chemotherapy compared with diagnosis, and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes cytarabine resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive mitochondrial stress response. Finally, genetic and pharmacologic inhibition of CD39 ecto-ATPase activity blocks the mitochondrial reprogramming triggered by cytarabine treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML. Significance: Extracellular ATP and CD39–P2RY13–cAMP–OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML. This article is highlighted in the In This Issue feature, p. 1426
Published: 2020
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16. Combinatory therapy targeting mitochondrial oxidative phosphorylation improves efficacy of IDH mutant inhibitors in acute myeloid leukemia

Author: Floriant Bellvert, Camille Montersino, Pierre-Luc Mouchel, Brandon Nicolay, Guillaume Cazals, Laurent Fernando, Nicolas Broin, Jean-Charles Portais, Joe Marszalek, Clément Larrue, Norbert Vey, Sebastien Ronseaux, Thomas Farge, Jean-Emmanuel Sarry, Andrei Turtoi, Aliki Zavoriti, Tony Kaoma, Courtney D. DiNardo, Emeline Chu-Van, Claudie Bosc, Guillaume Cognet, Rémy Castellano, Héléna Boutzen, Cédric Cassan, Claire Calmettes, Florence Castelli, Marie Sabatier, Arnaud Pigneux, Evgenia Turtoi, Yves Collette, Martin Carroll, Yves Gibon, Emeline Boet, Laetitia K. Linares, Mathilde Gotanègre, Francois Fenaille, Laurent Le Cam, Lara Gales, Marc Conti, Nathalie Poupin, Mary A. Selak, Lucille Stuani, Andrew Futreal, Christian Recher, Marina Konopleva, Feng Wang, Estelle Saland, Mohsen Hosseini, Audrey Bidet, Kiyomi Morita, Natalia Baran, Koichi Takahashi, Sylvain Loric, Pierre Bories, Fabien Jourdan, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The University of Texas M.D. Anderson Cancer Center [Houston], Métabolisme et Xénobiotiques (ToxAlim-MeX), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Métabolomique et Fluxomique (MetaToul) (TBI-MetaToul), MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Luxembourg Institute of Health (LIH), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du fruit et pathologie (BFP), Université de Bordeaux (UB)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut du Cancer de Montpellier (ICM), Department of Medicine, Division of Haematology–Oncology, University of Pennsylvania, University of Pennsylvania [Philadelphia], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU Bordeaux [Bordeaux], Laboratoire de Mesures Physiques, Université de Montpellier (UM), Réseau régional de cancérologie Onco-Occitanie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Agios Pharmaceuticals, MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Jourdan, Fabien, Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: 0303 health sciences, IDH1, Chemistry, Mutant, Myeloid leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oxidative phosphorylation, 3. Good health, Citric acid cycle, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Epigenetics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Beta oxidation, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology
Abstract: Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, BCL-2 dependence and susceptibility to mitochondrial inhibitors in cancer cells. Here we show that high sensitivity to mitochondrial oxidative phosphorylation (OxPHOS) inhibitors is due to an enhanced mitochondrial oxidative metabolism in cell lines, PDX and patients with acute myeloid leukemia (AML) harboring IDH mutation. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurs through the increase in methylation-driven CEBPα- and CPT1a-induced fatty acid oxidation, electron transport chain complex I activity and mitochondrial respiration in IDH1 mutant AML. Furthermore, an IDH mutant inhibitor that significantly and systematically reduces 2-HG oncometabolite transiently reverses mitochondrial FAO and OxPHOS gene signature and activities in patients who responded to the treatment and achieved the remission. However, at relapse or in patients who did not respond, IDH mutant inhibitor failed to block these mitochondrial properties. Accordingly, OxPHOS inhibitors such as IACS-010759 improve anti-AML efficacy of IDH mutant inhibitors alone and in combination with chemotherapyin vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant-positive AML patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.
Published: 2020

17. Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

Author: Quentin Heydt, Jean-Emmanuel Sarry, Nizar Serhan, Jan-Henrik Mikesch, Thomas Farge, Ambrine Sahal, Christian Récher, Clément Larrue, Christoph Schliemann, Marie Sabatier, Nesrine Aroua, Nathan Guiraud, Sarah Mouche, Emeline Boet, Marine Dubois, Lucille Stuani, Jerome Tamburini, François Vergez, Pierre-Luc Mouchel, Estelle Saland, Mathilde Gotanègre, Tony Kaoma, Claudie Bosc, Linus Angenendt, and Marie-Laure Nicolau-Travers
Subjects: Gene knockdown, business.industry, Myeloid leukemia, CALCRL, Cell cycle, Adrenomedullin, hemic and lymphatic diseases, Cytarabine, medicine, Cancer research, E2F1, Stem cell, business, medicine.drug
Abstract: Drug tolerant leukemic cell subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these Relapse-Initiating Cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncovered that the G-protein coupled receptor CALCRL is expressed in leukemic stem cells (LSCs) and RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM) and not CGRP correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency and sensitizes to cytarabine in patient-derived xenograft (PDX) models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.
Published: 2020
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18. 3095 – OXPHOS-DRIVEN LEUKEMIC STEM CELLS ARE UNIQUELY SENSITIVE TO COLD EXPOSURE

Author: Emmanuel Griessinger, Marielle Nebout, Diego Pereira-Martins, Claudie Bosc, Estelle Saland, Emilie Boet, Ambrine Sahal, Johanna Chiche, Delphine Debayle, Lucille Fleuriot, Véronique DeMas, François Vergez, Christian Récher, Gerwin Huls, Jean-Emmanuel Sarry, Jan Jacob Schuringa, and Jean-François Peyron
Subjects: Cancer Research, Genetics, Cell Biology, Hematology, Molecular Biology
Published: 2022
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19. Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

Author: Thomas Farge, Marie-Virginie Larcher, Françoise Huguet, Estelle Saland, Suzanne Tavitian, Emilie Bérard, Audrey Sarry, Mauricette Michallet, François Vergez, Sarah Bertoli, Claudie Bosc, Etienne Paubelle, Jean-Emmanuel Sarry, Eric Delabesse, Xavier Thomas, Christian Recher, and Clément Larrue
Subjects: Adult, Male, Kaplan-Meier Estimate, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Odds Ratio, Humans, Medicine, FTH1, Aged, Proportional Hazards Models, biology, Gene Expression Regulation, Leukemic, business.industry, Gene Expression Profiling, Induction chemotherapy, Myeloid leukemia, Hematology, General Medicine, Middle Aged, Gene signature, Prognosis, Combined Modality Therapy, Ferritin, Leukemia, Myeloid, Acute, Haematopoiesis, Treatment Outcome, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Apoferritins, Ferritins, biology.protein, Cancer research, Cytarabine, Female, Inflammation Mediators, Stem cell, Oxidoreductases, business, Biomarkers, 030215 immunology, medicine.drug
Abstract: Objectives We previously reported the prognostic value of serum ferritin in younger patients with intermediate-risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients. Patients/materials/methods Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML. Results We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf-KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine-resistant AML cells in a patient-derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone. Conclusion Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.
Published: 2018
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20. Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia

Author: Francisco Azuale, Margherita Ghisi, Fetta Mazed, Claudie Bosc, Marie-Laure Nicolau-Travers, François Vergez, Thomas Farge, Mathilde Gotanègre, Jean-Emmanuel Sarry, Jerome Tamburini, Nesrine Aroua, Clément Larrue, Jean-Charles Portais, Floriant Bellvert, Pierre-Luc Mouchel, Christian Récher, Massimiliano Bardotti, Fabienne De Toni, Camille Laurent, Emeline Boet, Marie Sabatier, Lucille Stuani, Nathalie Bonnefoy, Charlotte Syrykh, Ryan Gwilliam, Tony Kaoma, Latifa Jarrou, Sarah Gandarillas, Estelle Saland, Nathalie Nicot, and Mohsen Hosseini
Subjects: Chemotherapy, business.industry, medicine.medical_treatment, Cell, Myeloid leukemia, medicine.anatomical_structure, Downregulation and upregulation, Cell culture, In vivo, hemic and lymphatic diseases, Cancer research, medicine, Cytarabine, business, Cytotoxicity, medicine.drug
Abstract: Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine (AraC)-resistant leukemic cells from both AML cell lines and patient samplesin vivoandin vitro. CD39 cell surface expression and activity is increased in AML patients upon chemotherapy compared to diagnosis and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes AraC resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated response. Finally, genetic and pharmacological inhibition of CD39 eATPase activity blocks the mitochondrial reprogramming triggered by AraC treatment and markedly enhances its cytotoxicity in AML cellsin vitroandin vivo. Together, these results reveal CD39 as a new prognostic marker and a promising therapeutic target to improve chemotherapy response in AML.SIGNIFICANCEExtracellular ATP and CD39-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML.
Published: 2019
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21. Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

Author: Claudie Bosc, Jean-Emmanuel Sarry, Marc Piechaczyk, Thomas Farge, Sonia Zaghdoudi, Mohsen Hosseini, Hamid Reza Rezvani, Véronique Guyonnet-Duperat, Clément Larrue, Mathilde Gotanègre, Nesrine Aroua, Pierre Luc Mouchel, Latifa Jarrou, Marie Sabatier, Christian Recher, Guillaume Bossis, Estelle Saland, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Transfert de gènes à visée thérapeutique dans les cellules souches, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de vectorologie, Université Bordeaux Segalen - Bordeaux 2-SFR TransBioMed, Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Cancer Research, Myeloid, [SDV]Life Sciences [q-bio], Apoptosis, Mice, SCID, medicine.disease_cause, Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, Molecular Targeted Therapy, RNA, Neoplasm, RNA, Small Interfering, ComputingMilieux_MISCELLANEOUS, Membrane Potential, Mitochondrial, chemistry.chemical_classification, biology, Chemistry, Cytarabine, Myeloid leukemia, Mitochondria, Neoplasm Proteins, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Myeloperoxidase, Oxidation-Reduction, medicine.drug, Antimetabolites, Antineoplastic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oxidative phosphorylation, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Peroxidase, Reactive oxygen species, Gene Expression Profiling, medicine.disease, Xenograft Model Antitumor Assays, Hypochlorous Acid, Oxidative Stress, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, biology.protein, Reactive Oxygen Species, Transcriptome, Oxidative stress
Abstract: Chemotherapies alter cellular redox balance and reactive oxygen species (ROS) content. Recent studies have reported that chemoresistant cells have an increased oxidative state in hematologic malignancies. In this study, we demonstrated that chemoresistant acute myeloid leukemia (AML) cells had a lower level of mitochondrial and cytosolic ROS in response to cytarabine (AraC) and overexpressed myeloperoxidase (MPO), a heme protein that converts hydrogen peroxide to hypochlorous acid (HOCl), compared with sensitive AML cells. High MPO-expressing AML cells were less sensitive to AraC in vitro and in vivo. They also produced higher levels of HOCl and exhibited an increased rate of mitochondrial oxygen consumption when compared with low MPO-expressing AML cells. Targeting MPO expression or enzyme activity sensitized AML cells to AraC treatment by triggering oxidative damage and sustaining oxidative stress, particularly in high MPO-expressing AML cells. This sensitization stemmed from mitochondrial superoxide accumulation, which impaired oxidative phosphorylation and cellular energetic balance, driving apoptotic death and selective eradication of chemoresistant AML cells in vitro and in vivo. Altogether, this study uncovers a noncanonical function of MPO enzyme in maintaining redox balance and mitochondrial energetic metabolism, therefore affecting downstream pathways involved in AML chemoresistance. Significance: These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.
Published: 2019
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22. IDH1 Mutation Enhances Catabolic Flexibility and Mitochondrial Dependencies to Favor Drug Resistance in Acute Myeloid Leukemia

Author: Héléna Boutzen, Clément Larrue, Pierre Millard, Laurent Fernando, Laurent Le Cam, Laurie Gayte, Noémie Gadaud, Tony Kaoma, Pierre-Luc Mouchel, Evgenia Turtoi, Jean-Charles Portais, Nesrine Aroua, Justine Bertrand-Michel, Courtney Dinardo, Tony Lionel Palama, Yves Collette, Camille Montersino, Laure Tonini, Yves Gibon, Madi Y. Cissé, Cédric Cassan, Koichi Takahashi, Florence Castelli, Pierre Bories, Audrey Bidet, Joe Marszalek, Martin Carroll, Guillaume Cazals, Claire Calmettes, Arnaud Pigneux, Thomas Farge, Lucille Stuani, Feng Wang, Fabien Jourdan, Laetitia K. Linares, Mary A. Selak, Lara Gales, Andrew M. Futreal, Mathilde Gotanègre, Maud Heuillet, Kiyomi Morita, Jean-Emmanuel Sarry, Andrei Turtoi, Nicolas Broin, Christian Recher, Marina Konopleva, Mohsen Hosseini, Christophe Junot, Claudie Bosc, Emeline Chu-Van, Marine Fraisse, Nathalie Saint-Laurent, Lindsay Peyriga, Rémy Castellano, Estelle Saland, Natalia Baran, Norbert Vey, Frédéric Lopez, Floriant Bellvert, Marie Sabatier, and Nathalie Poupin
Subjects: Citric acid cycle, IDH1, Chemistry, Catabolism, Mutant, Myeloid leukemia, Metabolism, Oxidative phosphorylation, Reprogramming, Cell biology
Abstract: Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. We hypothesized that key metabolic fluxes are selectively reprogrammed to maintain biosynthetic homeostasis and lower drug responses in IDH mutant acute myeloid leukemia cells. Here we show that metabolic reprogramming initiated by IDH1 mutation leads to marked increases in glucose, glutamine and fatty acid catabolism that along with enhancement of wild-type IDH enzyme activity contribute to provision of α-KG required for 2-HG synthesis and to replenish Krebs cycle intermediates for biosynthetic reactions, oxygen consumption and ATP production. Mechanistically, this occurs through both methylation-driven CEBPα activation of FAO and reprogramming of systemic metabolic fluxes through other pathways that augment catabolic flexibility. Consequently, this catabolic flexibility enhances Krebs cycle and OxPHOS activities that are not necessarily rescued by IDH mutant inhibitors or 2-HG reduction. This renders IDH1 mutant cells more resistant to chemotherapeutics but more susceptible to mitochondrial inhibition. Our findings provide a scientific rationale for innovative combinatory targeted therapies to treat this subgroup of patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.
Published: 2018
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23. Resistance Is Futile: Targeting Mitochondrial Energetics and Metabolism to Overcome Drug Resistance in Cancer Treatment

Author: Claudie Bosc, Mary A. Selak, and Jean-Emmanuel Sarry
Subjects: 0301 basic medicine, Physiology, Regulator, Antineoplastic Agents, macromolecular substances, Oxidative phosphorylation, Drug resistance, Biology, Pharmacology, Oxidative Phosphorylation, 03 medical and health sciences, Mice, Neoplasms, medicine, Animals, Humans, Molecular Biology, Cancer, Cell Biology, Metabolism, Therapeutic resistance, medicine.disease, Xenograft Model Antitumor Assays, Cancer treatment, Mitochondria, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, Mitochondrial energetics
Abstract: Metabolism is a key regulator of cancer biology; however, its role in therapeutic resistance has remained largely unresolved. Several new studies disclose that mitochondrial metabolism and oxidative phosphorylation at least in part drive chemoresistance in cancer and thus have important implications for targeted and more effective chemotherapies.
Published: 2017

24. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism

Author: François Vergez, Marine Fraisse, Nicolas Broin, Thomas Farge, Robin L. Perry, Jean-Emmanuel Sarry, Audrey Sarry, Suzanne Tavitian, Stéphanie Cassant-Sourdy, Mayumi Sugita, Laetitia K. Linares, Jason S. Iacovoni, Claudie Bosc, Olivier Duchamp, Gwenn Danet-Desnoyers, Fabienne De Toni, Sarah J. Scotland, Y Barreira, Pierre Hirsch, Emmanuel Griessinger, Estelle Saland, Camille Montersino, Rémy Castellano, Héléna Boutzen, Nizar Serhan, Laurent Vallar, Martin Carroll, Christian Recher, Moshen Hosseini, Yves Collette, Lara Gales, François Delhommeau, Marion David, Marie-Laure Nicolau-Travers, Jean-Charles Portais, Nesrine Aroua, Lucille Stuani, Clément Larrue, Tony Kaoma, Tony Lionel Palama, Mary A. Selak, Barbara Garmy-Susini, Virginie Féliu, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), U1065 Centre Méditerranéen de Médecine Moléculaire, Université de Nice Sophia-Antipolis (UNSA), Oncodesign, UMS006 Service d'Experimentation Animale, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S938 CDR Saint-Antoine, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation ARC [SFI20121205478], Laboratoire d'Excellence Toulouse Cancer (TOUCAN) [ANR11-LABEX], Programme Hospitalo-Universitaire en Cancerologie (CAPTOR) [ANR11-PHUC0001], INCA [PLBIO 2012-105], Veterans Affairs Administration [1I01BX000918-01], NIH [1R01CA149566-01A1], Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe 11-E.Moyal/C.Toulas, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie clinique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Luxembourg Institute of Health (LIH), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncodesign Inc., Oncodesign Biotechnology®, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre Européen de Résonance Magnétique Nucléaire à Très Hauts Champs (CERMNTHC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service d'immunologie et hématologies biologiques [Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP], Service d'hématologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncodesign [Dijon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Linares, Laetitia, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: CD36 Antigens, 0301 basic medicine, Myeloid, cancerologie, Mitochondrion, human health, Oxidative Phosphorylation, Mice, pharmacotherapy, 0302 clinical medicine, protéine mitochondriale, chimiothérapie, leucemie, Cytarabine, leukemia, Myeloid leukemia, santé humaine, Mitochondria, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, oncologie, oncology, Neoplastic Stem Cells, Stem cell, medicine.drug, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Downregulation and upregulation, Cell Line, Tumor, medicine, Animals, Humans, Cell Lineage, chimiothérapie, oncologie, cancerologie, approche thérapeutique, leucemie, protéine mitochondriale, santé humaine, approche thérapeutique, medicine.disease, Xenograft Model Antitumor Assays, carbohydrates (lipids), 030104 developmental biology, Drug Resistance, Neoplasm, Cell culture, Cancer research, pharmacotherapy, oncology, leukemia, human health, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease. Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36–FAO–OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716–35. ©2017 AACR. See related commentary by Schimmer, p. 670. This article is highlighted in the In This Issue feature, p. 653
Published: 2017
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25. PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia

Author: Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Adrien Grenier, Jean-Emmanuel Sarry, Jerome Tamburini, Sarah Mouche, Lucille Stuani, Benoit Viollet, Rudy Birsen, Didier Bouscary, Pierre Sujobert, Justine Decroocq, Laury Poulain, Fetta Mazed, and Patrick Auberger
Subjects: biology, Kinase, Chemistry, Immunology, Autophagy, AMPK, Cell Biology, Hematology, mTORC1, Biochemistry, Protein kinase R, AMP-activated protein kinase, Cancer cell, Cancer research, biology.protein, Protein kinase A
Abstract: Acute myeloid leukemia (AML) is a myeloid progenitor-derived neoplasm of poor prognosis, particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies. Novel therapeutic approaches for AML are therefore critically needed. Adenosine monophosphate (AMP) activated protein kinase (AMPK) is a pleiotropic serine/threonine kinase promoting catabolism that represses anabolism and enhances autophagy in response to stress1. AMPK heterotrimers comprise catalytic α- and regulatory β- and γ-subunits, the latter harboring binding sites for AMP. Targets of AMPK include a host of metabolic pathway enzymes mediating carbohydrate, lipid and protein synthesis and metabolism. Accumulating evidence implicates AMPK in cancer biology, primarily as a tumor suppressor, although minimal AMPK activity may also be required for cancer cell growth under stress conditions2,3. Pharmacological activation of AMPK thus represents an attractive new strategy for targeting AML. We previously used the selective small molecule AMPK activator GSK621 to show that AMPK activation induces cytotoxicity in AML but not in normal hematopoietic cells, contingent on concomitant activation of the mammalian target of rapamycin complex 1 (mTORC1)4. However, the precise mechanisms of AMPK-induced AML cytotoxicity have remained unclear. We integrated gene expression profiling and bioinformatics proteomic analysis to identify the serine/threonine kinase PERK - one of the key effectors of the endoplasmic reticulum stress response - as a potential novel target of AMPK. We showed that PERK was directly phosphorylated by AMPK on at least two conserved residues (serine 439 and threonine 680) and that AMPK activators elicited a PERK/eIF2A signaling cascade independent of the endoplasmic reticulum stress response in AML cells. CRISPR/Cas9 depletion and complementation assays illuminated a critical role for PERK in apoptotic cell death induced by pharmacological AMPK activation. Indeed, GSK621 induced mitochondrial membrane depolarization and apoptosis in AML cells, an effect that was mitigated when cells were depleted of PERK or expressed PERK with a loss of function AMPK phosphorylation site mutation. We identified the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) as a downstream target of the AMPK/PERK pathway, as its expression was enhanced in PERK knockdown AML cells. Moreover, selective pharmacologic activation of ALDH2 by the small molecule ALDA-1 recapitulated the protective effects of PERK depletion in the face of pharmacological AMPK activation. Corroborating the impact of the AMPK/PERK axis on mitochondrial apoptotic function, BH3 profiling showed marked Bcl-2 dependency in AML cells treated with GSK621. This dependency was abrogated in PERK-depleted cells, suggesting a role for PERK in mitochondrial priming to cell death. In vitro drug combination studies further demonstrated synergy between the clinical grade Bcl-2 inhibitor venetoclax (ABT-199) and each of four AMPK activators (GSK621, MK-8722, PF-06409577 and compound 991) in multiple AML cell lines. Finally, the addition of GSK621 to venetoclax enhanced anti-leukemic activity in primary AML patient samples ex vivo and in humanized mouse models in vivo. These findings together clarify the mechanisms of cytotoxicity induced by AMPK activation and suggest that combining pharmacologic AMPK activators with venetoclax may hold therapeutic promise in AML. References 1. Lin S-C, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism. 2018;27(2):299-313. 2. Hardie DG. Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clinical Cancer Research. 2015;21(17):3836-3840. 3. Jeon S-M, Hay N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 2015;38(3):346-357. 4. Sujobert P, Poulain L, Paubelle E, et al. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep. 2015;11(9):1446-1457. Figure Disclosures Tamburini: Novartis pharmaceutical: Research Funding; Incyte: Research Funding.
Published: 2019
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1. Adrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells

2. Autophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites

3. FAO-supported OxPhos leukemic stem cells are sensitive to cold

4. Supplementary Table S4 from Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

5. Supplementary Table S6 from Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

6. Supplementary Methods and Supplementary Figures 1 through 18 from Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

7. Supplementary Data from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

8. Supplementary Figures from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

9. Supplementary Methods from Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

10. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia

11. In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

12. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia

13. AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia

14. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia

15. Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

16. Combinatory therapy targeting mitochondrial oxidative phosphorylation improves efficacy of IDH mutant inhibitors in acute myeloid leukemia

17. Adrenomedullin-CALCRL Axis Controls Relapse-Initiating Drug Tolerant Acute Myeloid Leukemia Cells

18. 3095 – OXPHOS-DRIVEN LEUKEMIC STEM CELLS ARE UNIQUELY SENSITIVE TO COLD EXPOSURE

19. Ferritin heavy/light chain (FTH1/FTL) expression, serum ferritin levels, and their functional as well as prognostic roles in acute myeloid leukemia

20. Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia

21. Targeting Myeloperoxidase Disrupts Mitochondrial Redox Balance and Overcomes Cytarabine Resistance in Human Acute Myeloid Leukemia

22. IDH1 Mutation Enhances Catabolic Flexibility and Mitochondrial Dependencies to Favor Drug Resistance in Acute Myeloid Leukemia

23. Resistance Is Futile: Targeting Mitochondrial Energetics and Metabolism to Overcome Drug Resistance in Cancer Treatment

24. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism

25. PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia

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