Journal
CELL REPORTS
Volume 16, Issue 7, Pages 2003-2016Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.032
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Funding
- T. J. Martell Foundation
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- NIH [RO1-CA109355, RO1-CA164605, RO1-GM25232, R01-CA64140]
- Vanderbilt Digestive Disease Research grant [NIDDK P30DK58404]
- Vanderbilt-Ingram Cancer Center support grant [NCI P30CA68485]
- American Cancer Society [5 T32 CA009582-26, PF-13-303-01-DMC]
- National Center for Research Resources [UL1 RR024975-01]
- National Center for Advancing Translational Sciences [2 UL1 TR000445-06]
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Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8; 21) AML. PRO-seq also identified an enhancer 30 to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PROseq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
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