Journal
CANCER DISCOVERY
Volume 8, Issue 4, Pages 458-477Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0902
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Funding
- National Cancer Institute [K99/R00 CA208017, R01 CA177292, R01 CA206658, R01 CA214046, R35 CA198183]
- American Cancer Society [129863-RSG-16-158-01-CDD]
- Four Winds Foundation
- D. Warren Brown Foundation
- Connie Brown CLL Research Fund
- Sullivan CLL Research Foundation
- European Union's Seventh Framework Programme (FP7) [282510 BLUEPRINT]
- NCIP30 [CA 016058]
- OSU Comprehensive Cancer Center using Pelotonia funds
- [NCIP30 CA016058]
- NATIONAL CANCER INSTITUTE [R35CA197734, K99CA208017, R01CA177292, P30CA016058, R01CA214046] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM068412] Funding Source: NIH RePORTER
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Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers. SIGNIFICANCE: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. (C) 2018 AACR.
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