Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models.
Clement Larrue, Sarah Mouche, Paolo Angelino, Maxime Sajot, Rudy Birsen, Olivier Kosmider, Thomas Mckee, François Vergez, Christian Recher, Véronique Mansat-De Mas, Qiong Gu, Jun Xu, Petros Tsantoulis, Jean-Emmanuel Sarry, Jerome Tamburini
Author Information
Clement Larrue: Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland. ORCID
Sarah Mouche: Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland.
Paolo Angelino: Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland. ORCID
Maxime Sajot: Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France. ORCID
Rudy Birsen: Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland.
Olivier Kosmider: Université de Paris, Institut Cochin, CNRS U8104, Inserm U1016, 75014 Paris, France. ORCID
Thomas Mckee: Division of Clinical Pathology, Diagnostic Department, Geneva University Hospitals, 1205 Geneva, Switzerland. ORCID
François Vergez: Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France. ORCID
Christian Recher: Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France. ORCID
Véronique Mansat-De Mas: Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, 31100 Toulouse, France.
Qiong Gu: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. ORCID
Jun Xu: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. ORCID
Petros Tsantoulis: Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland. ORCID
Jean-Emmanuel Sarry: Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, 31100 Toulouse, France.
Jerome Tamburini: Centre for Translational Research in Onco-Hematology, Faculty of Medicine, University of Geneva, and Swiss Cancer Centre Leman, 1206 Geneva, Switzerland. ORCID
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 CD34CD38 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.
