Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism

Thomas Farge, Estelle Saland, Fabienne de Toni, Nesrine Aroua, Mohsen Hosseini, Robin Perry, Claudie Bosc, Mayumi Sugita, Lucille Stuani, Marine Fraisse, Sarah Scotland, Clément Larrue, Héléna Boutzen, Virginie Féliu, Marie Laure Nicolau-Travers, Stéphanie Cassant-Sourdy, Nicolas Broin, Marion David, Nizar Serhan, Audrey SarrySuzanne Tavitian, Tony Kaoma, Laurent Vallar, Jason Iacovoni, Laetitia K. Linares, Camille Montersino, Rémy Castellano, Emmanuel Griessinger, Yves Collette, Olivier Duchamp, Yara Barreira, Pierre Hirsch, Tony Palama, Lara Gales, François Delhommeau, Barbara H. Garmy-Susini, Jean Charles Portais, François Vergez, Mary Selak, Gwenn Danet-Desnoyers, Martin Carroll, Christian Récher, Jean Emmanuel Sarry*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

509 Citations (Scopus)

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 patientderived 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.

Original languageEnglish
Pages (from-to)716-735
Number of pages20
JournalCancer Discovery
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 2017

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