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Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor
Open accessAbstract
SUMMARY Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
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Tyner, J. W., Tognon, C. E., Bottomly, D., Wilmot, B., Kurtz, S. E., Savage, S. L., Long, N., Schultz, A. R., Traer, E., Abel, M., et al. (2018) · Nature · doi:10.1038/s41586-018-0623-z · Cited by 1,303
Metadata
- Authors
- Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Majer, C. R., Sneeringer, C. J., Song, J., Johnston, L. D., Scott, M. P., Smith, J. J., Xiao, Y., Jin, L., Kuntz, K. W., Chesworth, R., Moyer, M. P., Bernt, K. M., Tseng, J.-C., Kung, A. L., Armstrong, S. A., Copeland, R. A., Richon, V. M., & Pollock, R. M.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 20
- Issue
- 1
- Pages
- 53-65
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2091208410
- Cited by
- 923
- References
- 1
- FWCI
- 50.56
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Majer, C. R., Sneeringer, C. J., Song, J., Johnston, L. D., Scott, M. P., Smith, J. J., Xiao, Y., Jin, L., Kuntz, K. W., Chesworth, R., Moyer, M. P., Bernt, K. M., Tseng, J.-C., Kung, A. L., Armstrong, S. A., Copeland, R. A., . . . Pollock, R. M. (2011). Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor. Cancer Cell. https://doi.org/10.1016/j.ccr.2011.06.009
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
