BET bromodomain inhibitors in leukemia.

The last few years have seen the identification of bromodomain and extraterminal (BET) proteins as critical mediators of transcription with effects on its direct control and cisregulation. This discovery is important in furthering our understanding of the mechanisms of normal transcriptional control. Subsequent work has shed light on the multiple roles of BET proteins in various aberrant transcriptional pathways that have significant implications across many malignant cell types and other disease processes. Accordingly, considerable effort has been made to assess the utility of targeting BET proteins with specific small molecules in acute leukemia and across other types of cancer. In this review, we will discuss the most recent advances in our understanding of the mechanistic actions of BET proteins in normal transcriptional control, both at the gene body and cisregulatory elements; how this is subverted; and its aberrant downstream effects, specifically in the context of acute leukemia and other hematologic cancers. In particular, we will focus on altered epigenetic programs that have been shown to be central to the development and maintenance of acute myeloid leukemia in preclinical models. Finally, we will explore how the use of small-molecule BET inhibitors in leukemias has demonstrated significant promise in numerous single-agent and combination therapy preclinical models and will highlight efforts to translate this promise to the therapeutic arena through various clinical trials attempting to validate efficacy and safety. The considerable opportunities in epigenetically targeting leukemias through BET inhibition will undoubtedly play an important role in improving the management of these conditions in the future.