1. Inhibition of ubiquitin-specific protease 7 sensitizes acute myeloid leukemia to chemotherapy
- Author
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Pierre-Luc Mouchel, Laure David, Jean-Emmanuel Sarry, Véronique Mansat-De Mas, Sarah Bertoli, Maëlle Cartel, Mathilde Gotanègre, Stéphane Manenti, Arnaud Besson, Christine Didier, 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), Équipe labellisée Ligue Nationale Contre le Cancer [Toulouse], Ligue Nationale Contre le Cancer [Paris] (LNCC), 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), Institut de Recherche en Santé Digestive (IRSD ), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), 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)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ligue nationale contre le cancer, SEGUIN, Nathalie, 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)
- Subjects
Male ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Apoptosis ,Mice, SCID ,Ubiquitin-Specific Peptidase 7 ,Transcriptome ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,RNA, Small Interfering ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Cytarabine ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,3. Good health ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Leukemia, Myeloid, Acute ,Oncology ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Cell signalling ,medicine.drug ,Antimetabolites, Antineoplastic ,Programmed cell death ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,Chemotherapy ,business.industry ,Cell growth ,Gene Expression Profiling ,Gene signature ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cell culture ,Cancer research ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Resistance of acute myeloid leukemia (AML) to therapeutic agents is frequent. Consequently, the mechanisms leading tothis resistance must be understood and addressed. In this paper, we demonstrate that inhibition of deubiquitinylaseUSP7 significantly reduces cell proliferation in vitro and in vivo, blocks DNA replication progression and increases celldeath in AML. Transcriptomic dataset analyses reveal that a USP7 gene signature is highly enriched in cells from AMLpatients at relapse, as well as in residual blasts from patient-derived xenograft (PDX) models treated with clinically relevantdoses of cytarabine, which indicates a relationship between USP7 expression and resistance to therapy. Accordingly, singlecellanalysis of AML patient samples at relapse versus at diagnosis showed that a gene signature of the pre-existingsubpopulation responsible for relapse is enriched in transcriptomes of patients with a high USP7 level. Furthermore, wefound that USP7 interacts and modulates CHK1 protein levels and functions in AML. Finally, we demonstrated that USP7inhibition acts in synergy with cytarabine to kill AML cell lines and primary cells of patients with high USP7 levels.Altogether, these data demonstrate that USP7 is both a marker of resistance to chemotherapy and a potential therapeutictarget in overcoming resistance to treatment.
- Published
- 2020