@article{1707ee2eb8134fa8b4b406439b9991eb,
title = "High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML",
abstract = "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 3′ to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq 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.",
author = "Yue Zhao and Qi Liu and Pankaj Acharya and Stengel, {Kristy R.} and Quanhu Sheng and Xiaofan Zhou and Hojoong Kwak and Fischer, {Melissa A.} and Bradner, {James E.} and Strickland, {Stephen A.} and Mohan, {Sanjay R.} and Savona, {Michael R.} and Venters, {Bryan J.} and Zhou, {Ming Ming} and Lis, {John T.} and Hiebert, {Scott W.}",
note = "Funding Information: We thank all the members of S.W.H. lab for helpful discussions, reagents, and advice. We thank the Translational Pathology, the Hematological Sample Repository, Flow Cytometry, and VANTAGE Shared Resources for services and support. This work was supported by the T. J. Martell Foundation, the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, NIH grants (RO1-CA109355, RO1-CA164605, RO1-GM25232 and R01-CA64140), and core services performed through a Vanderbilt Digestive Disease Research grant (NIDDK P30DK58404) and a Vanderbilt-Ingram Cancer Center support grant (NCI P30CA68485). K.S. was supported by 5 T32 CA009582-26 and a postdoctoral fellowship (PF-13-303-01-DMC) from the American Cancer Society. The project described was also supported by the National Center for Research Resources (grant UL1 RR024975-01) and is now at the National Center for Advancing Translational Sciences (grant 2 UL1 TR000445-06). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = aug,
day = "16",
doi = "10.1016/j.celrep.2016.07.032",
language = "English (US)",
volume = "16",
pages = "2003--2016",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}