Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models

Article Article scientifique Article Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models eng 2024-07-24 2024-07-24 author Larrue Clément 0000-0001-5827-8433 Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland.,Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France.,LabEx Toucan, 31100 Toulouse, France.,Équipe labellisée Ligue Nationale Contre le Cancer 2023, 31100 Toulouse, France. 911116 author Mouche Sarah Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland. 103490 Département de médecine (DEMED) author Angelino Paolo 0000-0002-1037-2823 Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland.,Translational Data Science, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. 417124 author Sajot Maxime 0009-0005-1189-4913 Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France.,LabEx Toucan, 31100 Toulouse, France.,Équipe labellisée Ligue Nationale Contre le Cancer 2023, 31100 Toulouse, France. author Birsen Rudy Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland.,Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, 75014 Paris, France. 953605 author Kosmider Olivier 0000-0002-6021-4057 Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, 75014 Paris, France. author Mckee Thomas Alexander 0000-0002-2147-3136 Division of Clinical Pathology, Diagnostic Department, Geneva University Hospitals, 1205 Geneva, Switzerland. 549937 author Vergez François 0000-0002-0063-4404 Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France. author Recher Christian 0000-0002-3332-4525 Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France. author Mas Véronique Mansat-De Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France. author Gu Qiong 0000-0001-6011-3697 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. author Xu Jun 0000-0002-1075-0337 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. author Tsantoulis Petros 0000-0003-3613-6682 Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland. 861166 Département de médecine (DEMED) author Sarry Jean-Emmanuel Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France.,LabEx Toucan, 31100 Toulouse, France.,Équipe labellisée Ligue Nationale Contre le Cancer 2023, 31100 Toulouse, France. author Tamburini Bonnefoy Jérôme 0000-0002-0167-5996 Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland.,Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France.,Oncology Department, Geneva University Hospitals, 1205 Geneva, Switzerland. 909914 Département de médecine (DEMED) eadk1731 10.1126/scitranslmed.adk1731 39047119 1946-6234 https://www.science.org/doi/10.1126/scitranslmed.adk1731 Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Leukemic stem cells (LSCs) contribute to therapeutic failure, relapse, and adverse outcome. This study investigates the role of quiescence and related molecular mechanisms in AML pathogenesis and LSC functions to identify potential therapeutic targets. Transcriptomic analysis revealed that the LSC-enriched quiescent cell population has a distinct gene signature with prognostic relevance in patients with AML. Mechanistically, quiescent blasts exhibit increased autophagic activity, which contributes to their sustained viability. Proteomic profiling uncovered differential requirements for iron metabolism between quiescent and cycling cells, revealing a unique dependence of quiescent cells on ferritinophagy, a selective form of autophagy mediated by nuclear receptor coactivator 4 (NCOA4), which regulates iron bioavailability. We evaluated the therapeutic potential of inhibiting NCOA4-mediated ferritinophagy using genetic knockdown and chemical inhibition approaches. In vitro assays showed that suppression of NCOA4 was toxic to leukemic blasts, particularly the CD34+ CD38- LSC-enriched population, without affecting normal CD34+ hematopoietic progenitors. In vivo studies using murine patient-derived xenograft (PDX) models of AML confirmed that NCOA4 inhibition reduced tumor burden and impaired LSC viability and self-renewal, indicating a specific vulnerability of these cells to ferritinophagy disruption. Our findings underscore the role of NCOA4-mediated ferritinophagy in maintaining LSC quiescence and function and suggest that targeting this pathway may be an effective therapeutic strategy for AML. This study highlights the potential of NCOA4 inhibition to improve AML outcomes and paves the way for future research and clinical development. Leukemia, Myeloid, Acute / pathology Leukemia, Myeloid, Acute / metabolism Neoplastic Stem Cells / metabolism Neoplastic Stem Cells / pathology Humans Animals Autophagy Ferritins / metabolism Nuclear Receptor Coactivators / metabolism Mice Cell Line, Tumor Iron / metabolism Xenograft Model Antitumor Assays Dewey 616.07 Dewey 616 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 503 SERVICE DE PATHOLOGIE CLINIQUE 841 476 Lymphomes MALT et réplication virale 807 1257 Lymphomes et leucémies 994 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235070 https://www.ebi.ac.uk/pride/archive/projects/PXD042796 https://zenodo.org/records/11643829 Science translational medicine 16 757 d3a31f50-a28b-4e97-8509-8b149d5bd0c1 Article (Published version) Restricted scitranslmed.adk1731.pdf 12401678 application/pdf 24ae2b6e6b88e7edc2ddd7a1bf4332ceefe45c3e18357ff06b70e01428b8b9d5 e4ae4990-d358-4686-8a59-224e3b7aa295 Supplemental data Restricted scitranslmed.adk1731_mdar_reproduci.pdf 490432 application/pdf 2b6fc21b073de42bf85c75550ce5879a65275f3f8b2c16450b2b7c8c9d91b58c f23a2ef9-9f37-459e-a9c4-37362d030c9a Supplemental data Restricted scitranslmed.adk1731_sm.pdf 2089377 application/pdf 94bd4049b6530b8b574b5c425bb0ecf6c29a16b1ce04488cb2423b838e0b5c02 199023e2-1612-4d68-be41-13824cfcb375 Supplemental data Restricted scitranslmed.adk1731_data_files_s1_.zip 414527 application/zip 48784f728dcc7e1967c42c055b7d2102b3038bf3feea0f72811b95c4c8957961 restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

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