The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia
Open accessAbstract
We investigated the therapeutic potential of JQ1, an inhibitor of the BET class of human bromodomain proteins, in B-cell acute lymphoblastic leukemia (B-ALL). We show that JQ1 potently reduces the viability of B-ALL cell lines with high-risk cytogenetics. Among the most sensitive were lines with rearrangements of CRLF2, which is overexpressed in ∼ 10% of B-ALL. CRLF2 heterodimerizes with the IL7 receptor (IL7R) and signals through JAK2, JAK1, and STAT5 to drive proliferation and suppress apoptosis. As previously observed, JQ1 induced the down-regulation of MYC transcription, the loss of BRD4 at the MYC promoter, and the reduced expression of c-Myc target genes. Strikingly, JQ1 also down-regulated IL7R transcription, depleted BRD4 from the IL7R promoter, and reduced JAK2 and STAT5 phosphorylation. Genome-wide expression profiling demonstrated a restricted effect of JQ1 on transcription, with MYC and IL7R being among the most down-regulated genes. Indeed, IL7R was the only cytokine receptor in CRLF2-rearranged B-ALL cells significantly down-regulated by JQ1 treatment. In mice xenografted with primary human CRLF2-rearranged B-ALL, JQ1 suppressed c-Myc expression and STAT5 phosphorylation and significantly prolonged survival. Thus, bromodomain inhibition is a promising therapeutic strategy for B-ALL as well as other conditions dependent on IL7R signaling.
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Selective inhibition of BET bromodomains
Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W. B., Fedorov, O., Morse, E. M., Keates, T., Hickman, T. T., Felletar, I., et al. (2010) · Nature · doi:10.1038/nature09504 · Cited by 4,262
Self-citationDeletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia
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Chapuy, B., McKeown, M. R., Lin, C. Y., Monti, S., Roemer, M. G. M., Qi, J., Rahl, P. B., Sun, H. H., Yeda, K. T., Doench, J. G., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.11.003 · Cited by 735
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Metadata
- Authors
- Ott, C. J., Kopp, N., Bird, L., Paranal, R. M., Qi, J., Bowman, T., Rodig, S. J., Kung, A. L., Bradner, J. E., & Weinstock, D. M.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-10-04
- Volume
- 120
- Issue
- 14
- Pages
- 2843-2852
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2162696088
- Cited by
- 374
- References
- 7
- FWCI
- 15.10
- Type
- journal article
- Language
- en
- Open access
- green
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- Ott, C. J., Kopp, N., Bird, L., Paranal, R. M., Qi, J., Bowman, T., Rodig, S. J., Kung, A. L., Bradner, J. E., & Weinstock, D. M. (2012). BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. https://doi.org/10.1182/blood-2012-02-413021
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