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

Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
Cell Rep. 2016 16 (7): 2003-16

PMID: 27498870 · PMCID: PMC4996374 · DOI:10.1016/j.celrep.2016.07.032

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.

Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

MeSH Terms (23)

Antineoplastic Agents Azepines Cell Line, Tumor Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 21 Clustered Regularly Interspaced Short Palindromic Repeats DNA-Directed RNA Polymerases Drug Resistance, Neoplasm Enhancer Elements, Genetic Gene Expression Regulation, Leukemic High-Throughput Nucleotide Sequencing Humans Leukemia, Myeloid, Acute MicroRNAs Multigene Family Myeloid Cell Leukemia Sequence 1 Protein Promoter Regions, Genetic Protein Isoforms Proteins Proto-Oncogene Proteins c-kit Transcription, Genetic Translocation, Genetic Triazoles

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