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Review
. 2016 Sep 28:9:5943-5953.
doi: 10.2147/OTT.S100515. eCollection 2016.

BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects

Sameem M Abedin  1 , Craig S Boddy  1 , Hidayatullah G Munshi  2
Affiliations
Review

BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects

Sameem M Abedin et al. Onco Targets Ther. .

Abstract

The bromodomain and extra-terminal (BET) family of proteins are important epigenetic regulators involved in promoting gene expression of critical oncogenes. BET inhibitors have been demonstrated to repress c-Myc expression, and were initially shown to have efficacy in a number of c-Myc-dependent hematologic malignancies. Recent studies have now revealed a broader role for BET inhibitors in hematologic malignancies. In this review, we summarize the efficacy of BET inhibitors in preclinical models of acute leukemia, lymphoma, and multiple myeloma. We also summarize recent results of clinical trials utilizing BET inhibitors in hematologic malignancies, characterize potential resistance mechanisms to BET inhibitors, and discuss potential combination therapies with BET inhibitors in patients with hematologic malignancies.

Keywords: leukemia; lymphoma; multiple myeloma; resistance mechanisms; toxicity.

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Figures

Figure 1
Figure 1
Transcriptional activation by BRD4. Binding of BRD4 to acetylated histones recruits the P-TEFb complex, which contains CDK9 and cyclin T, to acetylated histones. BRD4 recruits transcriptional effectors and mediates activation of P-TEFb by displacing HEXIM1. The activated P-TEFb in turn phosphorylates and activates RNA polymerase II to initiate gene transcription. Small-molecule inhibitors, such as JQ1 and I-BET151, compete with the acetyl-binding pockets present in the bromodomains of BET proteins and block BET-dependent gene expression. Abbreviations: BET, bromodomain and extra-terminal; SEC, super elongation complex; PAFc, polymerase-associated factor complex.
See this image and copyright information in PMC

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