| Literature DB >> 28416471 |
Thomas Farge1,2,3, Estelle Saland1,2,3, Fabienne de Toni1,2,3, Nesrine Aroua1,2,3, Mohsen Hosseini1,2, Robin Perry4, Claudie Bosc1,2, Mayumi Sugita4, Lucille Stuani1,2, Marine Fraisse1,2, Sarah Scotland1,2, Clément Larrue1,2, Héléna Boutzen1,2, Virginie Féliu1,2,5, Marie-Laure Nicolau-Travers1,2,6, Stéphanie Cassant-Sourdy7, Nicolas Broin1,2, Marion David1,2, Nizar Serhan1,2, Audrey Sarry8, Suzanne Tavitian6, Tony Kaoma9, Laurent Vallar9, Jason Iacovoni7, Laetitia K Linares10,11,12, Camille Montersino13,14,15,16, Rémy Castellano13,14,15,16, Emmanuel Griessinger17, Yves Collette13,14,15,16, Olivier Duchamp3,18, Yara Barreira3,19, Pierre Hirsch5,20,21,22, Tony Palama23,24,25, Lara Gales23,24,25, François Delhommeau5,20,21,22, Barbara H Garmy-Susini7, Jean-Charles Portais23,24,25, François Vergez1,2,3, Mary Selak4, Gwenn Danet-Desnoyers4, Martin Carroll4, Christian Récher1,2,3,6, Jean-Emmanuel Sarry26,2,3.
Abstract
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. ©2017 American Association for Cancer Research.Entities:
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Year: 2017 PMID： 28416471 PMCID： PMC5501738 DOI： 10.1158/2159-8290.CD-16-0441
Source DB: PubMed Journal: Cancer Discov ISSN： 2159-8274 Impact factor: 39.397