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Cancer Discov. 2017 Jul;7(7):716-735. doi: 10.1158/2159-8290.CD-16-0441. Epub 2017 Apr 17.

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

Author information

1
Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
2
Université de Toulouse, Toulouse, France.
3
Consortium IMODI "Innovative MODels Initiative against Cancer," France.
4
Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
5
Sorbonne Universités, UPMC Université Paris 06, UMR-S 938, CDR Saint-Antoine, Paris, France.
6
Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France.
7
Inserm, Institut des Maladies Métaboliques et Cardiovasculaires, U1048, Toulouse, France.
8
Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France. jean-emmanuel.sarry@inserm.fr.
9
Proteome and Genome Research Unit, Department of Oncology, Luxembourg Institute of Health, Strassen, Luxembourg.
10
Inserm, Institut de Recherche en Cancérologie de Montpellier, U1194, Montpellier, France.
11
Université de Montpellier, Montpellier, France.
12
Institut Régional du Cancer Montpellier, Montpellier, France.
13
Inserm, Centre de Recherche en Cancérologie de Marseille, U1068, Marseille, France.
14
Institut Paoli-Calmettes, Marseille, France.
15
Université Aix-Marseille, Marseille, France.
16
CNRS, UMR7258, Marseille, France.
17
Inserm, Centre Méditerranéen de Médecine Moléculaire, U1065, Nice, France.
18
Oncodesign, Dijon, France.
19
Inserm, Service d'Expérimentation Animale, UMS006, Toulouse, France.
20
Inserm, UMR-S938, CDR Saint-Antoine, Paris, France.
21
Sorbonne Universités, UPMC Université Paris 06, GRC n°07, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MyPAC, Paris, France.
22
AP-HP, Hôpital Saint-Antoine, Paris, France.
23
Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
24
INRA, UMR792, Ingénierie des Systèmes Biologiques & des Procédés, Toulouse, France.
25
CNRS, UMR5504, Toulouse, France.
26
Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France. jean-emmanuel.sarry@inserm.fr.

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.

PMID:
28416471
PMCID:
PMC5501738
DOI:
10.1158/2159-8290.CD-16-0441
[Indexed for MEDLINE]
Free PMC Article

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