The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia
Open accessAbstract
The identification of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL) led to clinical testing of γ-secretase inhibitors (GSIs) that prevent NOTCH1 activation. However, responses to these inhibitors have been transient, suggesting that resistance limits their clinical efficacy. Here we modeled T-ALL resistance, identifying GSI-tolerant 'persister' cells that expand in the absence of NOTCH1 signaling. Rare persisters are already present in naive T-ALL populations, and the reversibility of their phenotype suggests an epigenetic mechanism. Relative to GSI-sensitive cells, persister cells activate distinct signaling and transcriptional programs and exhibit chromatin compaction. A knockdown screen identified chromatin regulators essential for persister viability, including BRD4. BRD4 binds enhancers near critical T-ALL genes, including MYC and BCL2. The BRD4 inhibitor JQ1 downregulates expression of these targets and induces growth arrest and apoptosis in persister cells, at doses well tolerated by GSI-sensitive cells. Consistently, the GSI-JQ1 combination was found to be effective against primary human leukemias in vivo. Our findings establish a role for epigenetic heterogeneity in leukemia resistance that may be addressed by incorporating epigenetic modulators in combination therapy.
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Self-citationTranscriptional plasticity promotes primary and acquired resistance to BET inhibition
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Metadata
- Authors
- Knoechel, B., Roderick, J. E., Williamson, K. E., Zhu, J., Lohr, J. G., Cotton, M. J., Gillespie, S. M., Fernandez, D., Ku, M., Wang, H., Piccioni, F., Silver, S. J., Jain, M., Pearson, D., Kluk, M. J., Ott, C. J., Shultz, L. D., Brehm, M. A., Greiner, D. L., Gutierrez, A., Stegmaier, K., Kung, A. L., Root, D. E., Bradner, J. E., Aster, J. C., Kelliher, M. A., & Bernstein, B. E.
- Venue
- Nature Genetics
- Published
- 2014-03-02
- Volume
- 46
- Issue
- 4
- Pages
- 364-370
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1987835971
- Cited by
- 367
- References
- 9
- FWCI
- 38.61
- Type
- journal article
- Language
- en
- Open access
- green
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- Knoechel, B., Roderick, J. E., Williamson, K. E., Zhu, J., Lohr, J. G., Cotton, M. J., Gillespie, S. M., Fernandez, D., Ku, M., Wang, H., Piccioni, F., Silver, S. J., Jain, M., Pearson, D., Kluk, M. J., Ott, C. J., Shultz, L. D., Brehm, M. A., Greiner, D. L., . . . Bernstein, B. E. (2014). An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nature Genetics. https://doi.org/10.1038/ng.2913
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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.
