Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism
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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
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A recurrent theme in studies of cancer progression is increased reliance of cancer cells on OXPHOS in advanced stages of disease.
“A recurrent theme in studies on cancer progression is the increased reliance of cancer cells on OXPHOS in advanced stages of disease.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [115]
OXPHOS promotes resistance to cytarabine in mouse models of AML; cytarabine treatment spares cells with high OXPHOS, and cytarabine-resistant cells are susceptible to OXPHOS inhibitors.
“OXPHOS also promotes resistance to the antimetabolite cytarabine in mouse models of AML (115). Cells persisting after cytarabine treatment and preexisting cells with innate cytarabine resistance both displayed enhanced OXPHOS. Cytarabine treatment in AML-bearing mice spares cells with high levels of OXPHOS, and cytarabine-resistant cells are susceptible to OXPHOS inhibitors (115).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [115]
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Linking Metabolic Reprogramming, Plasticity and Tumor Progression
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- Authors
- Farge, T., Saland, E., de Toni, F., Aroua, N., Hosseini, M., Perry, R., Bosc, C., Sugita, M., Stuani, L., Fraisse, M., Scotland, S., Larrue, C., Boutzen, H., Féliu, V., Nicolau-Travers, M.-L., Cassant-Sourdy, S., Broin, N., David, M., Serhan, N., Sarry, A., Tavitian, S., Kaoma, T., Vallar, L., Iacovoni, J., Linares, L. K., Montersino, C., Castellano, R., Griessinger, E., Collette, Y., Duchamp, O., Barreira, Y., Hirsch, P., Palama, T., Gales, L., Delhommeau, F., Garmy-Susini, B. H., Portais, J.-C., Vergez, F., Selak, M., Danet-Desnoyers, G., Carroll, M., Récher, C., & Sarry, J.-E.
- Affiliations
- Inserm (FR)
- 1Inserm, Cancer Research Center of Toulouse, U1037, Toulouse, France.
- University of Pennsylvania (US)
- 7Inserm, Institut des Maladies Métaboliques et Cardiovasculaires, U1048, Toulouse, France.
- Centre Hospitalier Universitaire de Toulouse (FR)
- Luxembourg Institute of Health (LU)
- Université de Montpellier (FR)
- Centre National de la Recherche Scientifique (FR)
- 3Consortium IMODI “Innovative MODels Initiative against Cancer,” France.
- Corresponding author
- Sarry, Audrey
- Sarry, Jean-Emmanuel
- ORCID
- Farge, Thomas
- Saland, Estelle
- Aroua, Nesrine
- Hosseini, Mohsen
- Bosc, Claudie
- Sugita, Mayumi
- Stuani, Lucille
- Fraisse, Marine
- Larrue, Clément
- Boutzen, Héléna
- Féliu, Virginie
- Nicolau-Travers, Marie-Laure
- Broin, Nicolas
- Serhan, Nizar
- Tavitian, Suzanne
- Kaoma, Tony
- Vallar, Laurent
- Linares, Laetitia K.
- Montersino, Camille
- Castellano, Rémy
- Griessinger, Emmanuel
- Collette, Yves
- Hirsch, Pierre
- Palama, Tony
- Delhommeau, François
- Garmy-Susini, Barbara H.
- Portais, Jean-Charles
- Vergez, François
- Selak, Mary
- Danet-Desnoyers, Gwenn
- Carroll, Martin
- Récher, Christian
- Sarry, Jean-Emmanuel
- Venue
- Cancer Discovery
- Published
- 2017-07-01
- Volume
- 7
- Issue
- 7
- Pages
- 716-735
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5501738
- OpenAlex
- W2605757478
- Cited by
- 912
- References
- 77
- Citations by year
- 2026: 66 · 2025: 108 · 2024: 113 · 2023: 139 · 2022: 130 · 2021: 135 · 2020: 103 · 2019: 64 · 2018: 39 · 2017: 15
- FWCI
- 46.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Cancer Discovery (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX000918)
- Agence Nationale de la Recherche (ANR-11-PHUC-0001)
- National Cancer Institute (R01CA149566, R01CA198089)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- acute myeloid leukemia, chemoresistance, cytarabine resistance, leukemia stem cells, oxidative phosphorylation, fatty acid oxidation, CD36, mitochondrial metabolism, patient-derived xenografts, reactive oxygen species, residual disease, metabolic reprogramming
- MeSH terms
- Animals, Cytarabine, Humans, Mitochondria, Oxidative Phosphorylation, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, CD36 Antigens, Drug Resistance, Neoplasm, Cell Lineage, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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