The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
Open accessAbstract
Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1R132H mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG–mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.
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Cites
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Cited by
Tzelepis, K., Koike-Yusa, H., De Braekeleer, E., Li, Y., Metzakopian, E., Dovey, O. M., Mupo, A., Grinkevich, V., Li, M., Mazan, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.079 · Cited by 761
Pollyea, D. A., Stevens, B. M., Jones, C. L., Winters, A., Pei, S., Minhajuddin, M., D’Alessandro, A., Culp-Hill, R., Riemondy, K. A., Gillen, A. E., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0233-1 · Cited by 778
Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells
Jones, C. L., Stevens, B. M., D'Alessandro, A., Reisz, J. A., Culp-Hill, R., Nemkov, T., Pei, S., Khan, N., Adane, B., Ye, H., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.005 · Cited by 585
The BCL-2 arbiters of apoptosis and their growing role as cancer targets
Adams, J. M., & Cory, S. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.161 · Cited by 530
The cancer epigenome: Concepts, challenges, and therapeutic opportunities
Dawson, M. A. (2017) · Science · doi:10.1126/science.aam7304 · Cited by 377
Metadata
- Authors
- Chan, S. M., Thomas, D., Corces-Zimmerman, M. R., Xavy, S., Rastogi, S., Hong, W.-J., Zhao, F., Medeiros, B. C., Tyvoll, D. A., & Majeti, R.
- Venue
- Nature Medicine
- Published
- 2015-01-19
- Volume
- 21
- Issue
- 2
- Pages
- 178-184
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2066640259
- Cited by
- 577
- References
- 14
- FWCI
- 35.73
- Type
- journal article
- Language
- en
- Open access
- green
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