Journal
CANCER DISCOVERY
Volume 7, Issue 7, Pages 716-735Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-16-0441
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Funding
- Association Laurette Fugain (RESISTAML)
- Fondation ARC [SFI20121205478]
- Region Midi-Pyrenees
- program Investissement d'Avenir IMODI
- Laboratoire d'Excellence Toulouse Cancer (TOUCAN) [ANR11-LABEX]
- Programme Hospitalo-Universitaire en Cancerologie (CAPTOR [ANR11-PHUC0001]
- INCA [PLBIO 2012-105]
- INCA (METAML)
- Plan Cancer -BioSys (FLEXAML)
- Fondation Toulouse Cancer Sante (RESISTAML)
- Association La confrerie de la Feve
- Association G.A.E.L. MetaToul (Metabolomics AMP
- Fluxomics Facilities, Toulouse, France)
- European Regional Development Fund
- SICOVAL
- Infrastructures en Biologie Sante et Agronomie (IBiSa, France)
- Centre National de la Recherche Scientifique (CNRS)
- Institut National de la Recherche Agronomique (INRA)
- Veterans Affairs Administration [1I01BX000918-01]
- NIH [1R01CA149566-01A1]
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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. (C) 2017 AACR.
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