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Mitochondrial Oxphos As Survival Mechanism of Minimal Residual AML Cells after Induction Chemotherapy : Survival Benefit By Complex I Inhibition with Iacs-010759
Abstract
Acute myeloid leukemia (AML) is initiated and maintained by a relatively rare leukemia stem cells (LSCs) capable of self-renewal and proliferation. Recent data showed that LSCs (Lagadinou et al. Cell Stem Cell 2013) and residual cytarabine (Ara-C)-resistant AML cells (representing minimal residual disease, MRD) (Farge et al. Cancer Discovery 2017) are highly dependent on mitochondrial function for survival. This unique metabolic biology makes chemoresistant LSCs and AML cells vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS). We have reported that a novel OXPHOS inhibitor IACS-010759 potently inhibits mitochondrial complex I, suppresses OXPHOS and selectively inhibits the growth of AML cells in vitro and in vivo (Molina et al. Nat Med 2018). In this study, we aimed to determine the effects of OXPHOS inhibition with IACS-010759 on residual AML cells surviving standard chemotherapy (Doxorubicin/Ara-C, DA) in cell line and patient-derived xenograft (PDX) AML models. Consistent with our hypothesis, OCI-AML3 cells treated with DA in vitro induced elevated levels of reactive oxygen species, higher mitochondrial mass and membrane potential (Fig. 1A), indicating reliance on the mitochondrial metabolism. Further, Ara-C treatment resulted in significantly increased basal and maximal oxygen consumption rates (OCR) (36%±8%, p=0.03; 36%±3%, p=0.003, respectively) compared to control. In turn, targeting OXPHOS with IACS-010759 at 30 nM fully inhibited basal a…
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Treatment with mitochondrial inhibitors is associated with reduced HIF-1α protein levels under hypoxia.
“treatment with mitochondrial inhibitors - including rotenone, oligomycin, the complex I inhibitor IACS-010759, mitochondrial uncouplers, and clinically approved agents such as atovaquone and metformin, has been associated with reduced HIF-1α protein levels under hypoxia [[369], [370], [371], [372], [373], [374], [375]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [371]
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Metadata
- Authors
- Han, L., Cavazos, A., Baran, N., Zhang, Q., Kuruvilla, V. M., Gay, J. P., Feng, N., Battula, V. L., Kantarjian, H. M., Daver, N. G., Marszalek, J. R., Andreeff, M., & Konopleva, M. Y.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-11-13
- Volume
- 134
- Issue
- Supplement_1
- Pages
- 5161-5161
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2987185017
- Cited by
- 19
- References
- 0
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 3
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- acute myeloid leukemia, minimal residual disease, leukemia stem cells, oxidative phosphorylation inhibition, IACS-010759, mitochondrial complex I, doxorubicin, cytarabine, combination chemotherapy, patient-derived xenografts, reactive oxygen species, oxygen consumption rate, mitochondrial metabolism, leukemia survival, bioluminescence imaging, OCI-AML3
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