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 a new 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) that are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1400 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 and CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRN

ORGANISM(S): Homo sapiens

SUBMITTER: Scott Hiebert 

PROVIDER: E-GEOD-83660 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress