The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia
Open accessAbstract
Recent evidence suggests that inhibition of bromodomain and extra-terminal (BET) epigenetic readers may have clinical utility against acute myeloid leukemia (AML). Here we validate this hypothesis, demonstrating the efficacy of the BET inhibitor I-BET151 across a variety of AML subtypes driven by disparate mutations. We demonstrate that a common 'core' transcriptional program, which is HOX gene independent, is downregulated in AML and underlies sensitivity to I-BET treatment. This program is enriched for genes that contain 'super-enhancers', recently described regulatory elements postulated to control key oncogenic driver genes. Moreover, our program can independently classify AML patients into distinct cytogenetic and molecular subgroups, suggesting that it contains biomarkers of sensitivity and response. We focus AML with mutations of the Nucleophosmin gene (NPM1) and show evidence to suggest that wild-type NPM1 has an inhibitory influence on BRD4 that is relieved upon NPM1c mutation and cytosplasmic dislocation. This leads to the upregulation of the core transcriptional program facilitating leukemia development. This program is abrogated by I-BET therapy and by nuclear restoration of NPM1. Finally, we demonstrate the efficacy of I-BET151 in a unique murine model and in primary patient samples of NPM1c AML. Taken together, our data support the use of BET inhibitors in clinical trials in AML.
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Cites
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961
Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype
Falini, B., Mecucci, C., Tiacci, E., Alcalay, M., Rosati, R., Pasqualucci, L., La Starza, R., Diverio, D., Colombo, E., Santucci, A., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa041974 · Cited by 1,892
Suppression of inflammation by a synthetic histone mimic
Nicodeme, E., Jeffrey, K. L., Schaefer, U., Beinke, S., Dewell, S., Chung, C.-W., Chandwani, R., Marazzi, I., Wilson, P., Coste, H., et al. (2010) · Nature · doi:10.1038/nature09589 · Cited by 1,563
Self-citationTranscription factors in myeloid development: balancing differentiation with transformation
Rosenbauer, F., & Tenen, D. G. (2007) · Nature Reviews Immunology · doi:10.1038/nri2024 · Cited by 606
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Self-citationMolecular landscape of acute myeloid leukemia in younger adults and its clinical relevance
Grimwade, D., Ivey, A., & Huntly, B. J. P. (2016) · Blood · doi:10.1182/blood-2015-07-604496 · Cited by 445
Self-citationBromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study
Berthon, C., Raffoux, E., Thomas, X., Vey, N., Gomez-Roca, C., Yee, K., Taussig, D. C., Rezai, K., Roumier, C., Herait, P., et al. (2016) · The Lancet Haematology · doi:10.1016/s2352-3026(15)00247-1 · Cited by 420
Bromodomain inhibitors and cancer therapy: From structures to applications
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Coudé, M.-M., Braun, T., Berrou, J., Dupont, M., Bertrand, S., Masse, A., Raffoux, E., Itzykson, R., Delord, M., Riveiro, M. E., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4131 · Cited by 274
Metadata
- Authors
- Dawson, M. A., Gudgin, E. J., Horton, S. J., Giotopoulos, G., Meduri, E., Robson, S., Cannizzaro, E., Osaki, H., Wiese, M., Putwain, S., Fong, C. Y., Grove, C., Craig, J., Dittmann, A., Lugo, D., Jeffrey, P., Drewes, G., Lee, K., Bullinger, L., Prinjha, R. K., Kouzarides, T., Vassiliou, G. S., & Huntly, B. J. P.
- Venue
- Leukemia
- Published
- 2013-11-13
- Volume
- 28
- Issue
- 2
- Pages
- 311-320
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2001854096
- Cited by
- 175
- References
- 4
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- The paper
- Dawson, M. A., Gudgin, E. J., Horton, S. J., Giotopoulos, G., Meduri, E., Robson, S., Cannizzaro, E., Osaki, H., Wiese, M., Putwain, S., Fong, C. Y., Grove, C., Craig, J., Dittmann, A., Lugo, D., Jeffrey, P., Drewes, G., Lee, K., Bullinger, L., . . . Huntly, B. J. P. (2014). Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. https://doi.org/10.1038/leu.2013.338
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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