American Association for Cancer Research
Browse
21598290cd160441-sup-164075_2_unknown_upload_3967993_kk1kc3.xlsx (10.31 kB)

Supplementary Table S7 from Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism

Download (10.31 kB)
dataset
posted on 2023-04-03, 21:24 authored by 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 Sarry, Suzanne 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

Summary of all GSEA data identified in AraC- versus PBS-treated AML cells in PDX and LOW versus HIGH Responder to AraC in PDX.

Funding

Association Laurette Fugain

ARC

Région Midi-Pyrénées

IMODI

TOUCAN

Innovate UK

Find out more...

CAPTOR

INCA

FLEXAML

RESISTAML

CNRS

INRA

Veterans Affairs Administration

NIH

History

ARTICLE 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. 670.This article is highlighted in the In This Issue feature, p. 653