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Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

Thomas Farge 1 Estelle Saland 2 Fabienne de Toni 3 Nesrine Aroua 1 Mohsen Hosseini 1 Robin Perry Claudie Bosc 1 Mayumi Sugita 4 Lucille Stuani 5 Marine Fraisse 1 Sarah J. Scotland 6 Clément Larrue 5 Héléna Boutzen 5 Virginie Feliu 1 Marie-Laure Nicolau-Travers 7 Stéphanie Cassant-Sourdy 2 Nicolas Broin 1 Marion David 8 Nizar Serhan 2 Audrey Sarry 1 Suzanne Tavitian 1 Tony Kaoma 9 Laurent Vallar 9 Jason S. Iacovoni 10 Laetitia K. Linares 11 Camille Montersino 12 Remy Castellano 12 Emmanuel Griessinger 13 yves Collette 12 Olivier Duchamp 14 yara Barreira 15 Pierre Hirsch 16 Tony L Palama 17 Lara Gales 17 François Delhommeau 18 Barbara Garmy-Susini 2 Jean-Charles Portais 17 François Vergez 5 Mary Selak 4 Gwenn Danet-Desnoyers 4 Martin Carroll 4 Christian Recher 19 Jean-Emmanuel Sarry 1 
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.
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Submitted on : Monday, February 3, 2020 - 5:11:58 PM
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Thomas Farge, Estelle Saland, Fabienne de Toni, Nesrine Aroua, Mohsen Hosseini, et al.. Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer Discovery, American Association for Cancer Research, 2017, 7 (7), pp.716-735. ⟨10.1158/⟩. ⟨inserm-02465205⟩



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