BET inhibitors Induce Quiescence and Disrupt eRNA Synthesis in AML (PRO-Seq). Homo sapiens

Inhibitors of the bromodomain and extra-terminal domain family (BETi) offer a new approach to treating hematological malignancies, with leukemias containing MLL rearrangements being especially sensitive due to a reliance on the regulation of transcriptional elongation mediated by the BET family members BRD2, BRD3, and BRD4. In this regard, members of the ETO/MTG family that are disrupted by the t(8;21) in AML also associate with P-TEFb, which mediates associations with BRD4. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds affect cell size, trigger a rapid and reversible quiescence and, with time, cause cell death. Using precision nuclear run-on sequencing (PRO-Seq), we identified over 2000 genes in which transcription was affected within one hour of BETi treatment with roughly 90% of these genes showing impaired elongation and over 200 genes showing enhanced transcription including MCL1. PRO-Seq also identified over 2500 active enhancers with over 600 of these affected by BETi, including a 6th sub-enhancer in the MYC super-enhancer. Thus, PRO-Seq begins to define the mechanisms of transcriptional control of BETi in regulating cell cycle and metabolism.