High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML

Yue Zhao, Qi Liu, Pankaj Acharya, Kristy R. Stengel, Quanhu Sheng, Xiaofan Zhou, Hojoong Kwak, Melissa A. Fischer, James E. Bradner, Stephen A. Strickland, Sanjay R. Mohan, Michael R. Savona, Bryan J. Venters, Ming Ming Zhou, John T. Lis, Scott W. Hiebert

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2003-2016
Number of pages14
JournalCell Reports
Volume16
Issue number7
DOIs
StatePublished - Aug 16 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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