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Your search keyword '"Latifa Jarrou"' showing total 4 results
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4 results on '"Latifa Jarrou"'

1. 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

2. 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

3. 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

4. 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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