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Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia
- Source :
- Journal of Experimental Medicine, Journal of Experimental Medicine, 2021, 218 (5), pp.e20200924. ⟨10.1084/jem.20200924⟩, Journal of Experimental Medicine, Rockefeller University Press, 2021, 218 (5), ⟨10.1084/jem.20200924⟩, The Journal of Experimental Medicine
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- Stuani et al. demonstrate that IDH mutant AML cells display an enhanced mitochondrial phenotype, which is not reversed by IDH mutant inhibitors. This study provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.<br />Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.<br />Graphical Abstract
- Subjects :
- Pyridines
[SDV]Life Sciences [q-bio]
Mutant
Aminopyridines
Mice, SCID
Mitochondrion
medicine.disease_cause
Oxidative Phosphorylation
Epigenesis, Genetic
0302 clinical medicine
Piperidines
Mice, Inbred NOD
hemic and lymphatic diseases
Immunology and Allergy
Enzyme Inhibitors
Mice, Knockout
0303 health sciences
Mutation
Oxadiazoles
Chemistry
Triazines
Myeloid leukemia
Isocitrate Dehydrogenase
3. Good health
Mitochondria
[SDV] Life Sciences [q-bio]
Isoenzymes
Leukemia
Leukemia, Myeloid
030220 oncology & carcinogenesis
Doxycycline
Acute Disease
Immunology
Glycine
HL-60 Cells
[SDV.CAN]Life Sciences [q-bio]/Cancer
Article
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
Humans
Epigenetics
Protein kinase B
030304 developmental biology
medicine.disease
Xenograft Model Antitumor Assays
Leukemia & Lymphoma
Metabolism
Drug Resistance, Neoplasm
Cancer cell
Cancer research
Subjects
Details
- Language :
- English
- ISSN :
- 00221007 and 15409538
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental Medicine, Journal of Experimental Medicine, 2021, 218 (5), pp.e20200924. ⟨10.1084/jem.20200924⟩, Journal of Experimental Medicine, Rockefeller University Press, 2021, 218 (5), ⟨10.1084/jem.20200924⟩, The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....8dfb2b30f8b948c067d643d1119fbb0e