title: Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy.
abstract: Here we demonstrate that in a niche-like coculture system, cells from both primary and cultured acute myeloid leukemia (AML) sources take up functional mitochondria from murine or human bone marrow stromal cells. Using different molecular and imaging approaches, we show that AML cells can increase their mitochondrial mass up to 14%. After coculture, recipient AML cells showed a 1.5-fold increase in mitochondrial adenosine triphosphate production and were less prone to mitochondrial depolarization after chemotherapy, displaying a higher survival. This unidirectional transfer enhanced by some chemotherapeutic agents required cell-cell contacts and proceeded through an endocytic pathway. Transfer was greater in AML blasts compared with normal cord blood CD34(+) cells. Finally, we demonstrate that mitochondrial transfer was observed in vivo in an NSG immunodeficient mouse xenograft model and also occurred in human leukemia initiating cells and progenitors. As mitochondrial transfer provides a clear survival advantage following chemotherapy and a higher leukemic long-term culture initiating cell potential, targeting mitochondrial transfer could represent a future therapeutic target for AML treatment.
authors.affiliation: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Team 4 Inflammation, Cancer, Cancer Stem Cells, Nice, France; Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France;
authors.forename: Ruxanda
authors.initials: R
authors.lastname: Moschoi
authors.affiliation: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Team 4 Inflammation, Cancer, Cancer Stem Cells, Nice, France; Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France;
authors.forename: Véronique
authors.initials: V
authors.lastname: Imbert
authors.affiliation: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Team 4 Inflammation, Cancer, Cancer Stem Cells, Nice, France; Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France;
authors.forename: Marielle
authors.initials: M
authors.lastname: Nebout
authors.affiliation: Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France; INSERM U1065, C3M, Team 3, Regulation of caspase-dependent and -independent cell deaths, Nice, France;
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.affiliation: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Team 4 Inflammation, Cancer, Cancer Stem Cells, Nice, France; Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France;
authors.forename: Didier
authors.initials: D
authors.lastname: Mary
authors.affiliation: Département d'Onco-Hématologie, Institut Paoli-Calmette, Marseille, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Prebet
authors.affiliation: Team RESIST@ML-Chemoresistance, Stem Cells & Metabolism in AML, Cancer Research Center of Toulouse, Unité Mixte de Recherche Médicale (UMR) 1037, Toulouse, France;
authors.forename: Estelle
authors.initials: E
authors.lastname: Saland
authors.affiliation: Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France; Centre National de la Recherche Scientifique, UMR725, Marseille, France; Centre de Recherche en Cancérologie de Marseille, TrGET Platform, INSERM, U1068, Marseille, France; and.
authors.forename: Rémy
authors.initials: R
authors.lastname: Castellano
authors.affiliation: Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France; Centre National de la Recherche Scientifique, UMR725, Marseille, France; Centre de Recherche en Cancérologie de Marseille, TrGET Platform, INSERM, U1068, Marseille, France; and.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pouyet
authors.affiliation: Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France; Centre National de la Recherche Scientifique, UMR725, Marseille, France; Centre de Recherche en Cancérologie de Marseille, TrGET Platform, INSERM, U1068, Marseille, France; and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Collette
authors.affiliation: Département d'Onco-Hématologie, Institut Paoli-Calmette, Marseille, France;
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.affiliation: Département d'Onco-Hématologie, Institut Paoli-Calmette, Marseille, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Chabannon
authors.affiliation: Team RESIST@ML-Chemoresistance, Stem Cells & Metabolism in AML, Cancer Research Center of Toulouse, Unité Mixte de Recherche Médicale (UMR) 1037, Toulouse, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Recher
authors.affiliation: Team RESIST@ML-Chemoresistance, Stem Cells & Metabolism in AML, Cancer Research Center of Toulouse, Unité Mixte de Recherche Médicale (UMR) 1037, Toulouse, France;
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.affiliation: Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France; INSERM U1065, C3M, Microscopy Core Facility, Nice, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Alcor
authors.affiliation: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Team 4 Inflammation, Cancer, Cancer Stem Cells, Nice, France; Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France;
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Peyron
authors.affiliation: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Team 4 Inflammation, Cancer, Cancer Stem Cells, Nice, France; Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France;
authors.forename: Emmanuel
authors.identifier: 0000-0001-7529-4187
authors.initials: E
authors.lastname: Griessinger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D018920:Coculture Techniques; D018922:HL-60 Cells; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D020298:U937 Cells