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Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.
Farge, Thomas; Saland, Estelle; de Toni, Fabienne; Aroua, Nesrine; Hosseini, Mohsen; Perry, Robin; Bosc, Claudie; Sugita, Mayumi; Stuani, Lucille; Fraisse, Marine; Scotland, Sarah; Larrue, Clément; Boutzen, Héléna; Féliu, Virginie; Nicolau-Travers, Marie-Laure; Cassant-Sourdy, Stéphanie; Broin, Nicolas; David, Marion; Serhan, Nizar; Sarry, Audrey; Tavitian, Suzanne; Kaoma, Tony; Vallar, Laurent; Iacovoni, Jason; Linares, Laetitia K; Montersino, Camille; Castellano, Rémy; Griessinger, Emmanuel; Collette, Yves; Duchamp, Olivier; Barreira, Yara; Hirsch, Pierre; Palama, Tony; Gales, Lara; Delhommeau, François; Garmy-Susini, Barbara H; Portais, Jean-Charles; Vergez, François; Selak, Mary; Danet-Desnoyers, Gwenn; Carroll, Martin; Récher, Christian; Sarry, Jean-Emmanuel.
Afiliação
  • Farge T; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Saland E; Université de Toulouse, Toulouse, France.
  • de Toni F; Consortium IMODI "Innovative MODels Initiative against Cancer," France.
  • Aroua N; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Hosseini M; Université de Toulouse, Toulouse, France.
  • Perry R; Consortium IMODI "Innovative MODels Initiative against Cancer," France.
  • Bosc C; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Sugita M; Université de Toulouse, Toulouse, France.
  • Stuani L; Consortium IMODI "Innovative MODels Initiative against Cancer," France.
  • Fraisse M; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Scotland S; Université de Toulouse, Toulouse, France.
  • Larrue C; Consortium IMODI "Innovative MODels Initiative against Cancer," France.
  • Boutzen H; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Féliu V; Université de Toulouse, Toulouse, France.
  • Nicolau-Travers ML; Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Cassant-Sourdy S; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Broin N; Université de Toulouse, Toulouse, France.
  • David M; Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Serhan N; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Sarry A; Université de Toulouse, Toulouse, France.
  • Tavitian S; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Kaoma T; Université de Toulouse, Toulouse, France.
  • Vallar L; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Iacovoni J; Université de Toulouse, Toulouse, France.
  • Linares LK; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Montersino C; Université de Toulouse, Toulouse, France.
  • Castellano R; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Griessinger E; Université de Toulouse, Toulouse, France.
  • Collette Y; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Duchamp O; Université de Toulouse, Toulouse, France.
  • Barreira Y; Sorbonne Universités, UPMC Université Paris 06, UMR-S 938, CDR Saint-Antoine, Paris, France.
  • Hirsch P; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Palama T; Université de Toulouse, Toulouse, France.
  • Gales L; Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France.
  • Delhommeau F; Inserm, Institut des Maladies Métaboliques et Cardiovasculaires, U1048, Toulouse, France.
  • Garmy-Susini BH; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Portais JC; Université de Toulouse, Toulouse, France.
  • Vergez F; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Selak M; Université de Toulouse, Toulouse, France.
  • Danet-Desnoyers G; Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
  • Carroll M; Université de Toulouse, Toulouse, France.
  • Récher C; Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. jean-emmanuel.sarry@inserm.fr.
  • Sarry JE; Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France.
Cancer Discov ; 7(7): 716-735, 2017 07.
Article em En | MEDLINE | ID: mdl-28416471
Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease.Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36-FAO-OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716-35. ©2017 AACR.See related commentary by Schimmer, p. 670This article is highlighted in the In This Issue feature, p. 653.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Resistencia a Medicamentos Antineoplásicos / Citarabina / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Resistencia a Medicamentos Antineoplásicos / Citarabina / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article