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High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
- Source :
-
Cell reports [Cell Rep] 2016 Aug 16; Vol. 16 (7), pp. 2003-16. Date of Electronic Publication: 2016 Aug 04. - Publication Year :
- 2016
-
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.<br />Competing Interests: The authors have declared that no conflict of interest exists.<br /> (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents pharmacology
Azepines pharmacology
Cell Line, Tumor
Chromosomes, Human, Pair 21
Chromosomes, Human, Pair 8
Clustered Regularly Interspaced Short Palindromic Repeats
DNA-Directed RNA Polymerases metabolism
Drug Resistance, Neoplasm drug effects
Enhancer Elements, Genetic
High-Throughput Nucleotide Sequencing methods
Humans
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
MicroRNAs genetics
MicroRNAs metabolism
Multigene Family
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Promoter Regions, Genetic
Protein Isoforms antagonists & inhibitors
Protein Isoforms genetics
Protein Isoforms metabolism
Proteins genetics
Proteins metabolism
Proto-Oncogene Proteins c-kit metabolism
Transcription, Genetic
Triazoles pharmacology
DNA-Directed RNA Polymerases genetics
Drug Resistance, Neoplasm genetics
Gene Expression Regulation, Leukemic
Myeloid Cell Leukemia Sequence 1 Protein genetics
Proteins antagonists & inhibitors
Proto-Oncogene Proteins c-kit genetics
Translocation, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 16
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 27498870
- Full Text :
- https://doi.org/10.1016/j.celrep.2016.07.032