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. Cancer Discov; 8(4); 458–77. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 371

溴结构域和末端外 (BET) 家族蛋白是癌症基因表达的关键调节因子。在此，我们利用 BRD4 分析来识别参与慢性淋巴细胞白血病 (CLL) 发病机制的关键途径。 BRD4 在 CLL 中过度表达，并且在 CLL 中上调或从头表达的基因附近富集，这些基因在疾病发病机制和进展中具有已知的功能。这些基因，包括 B 细胞受体 (BCR) 信号通路的关键成员，为这种治疗方法确定替代类型癌症的新靶点提供了理论依据。此外，我们还描述了 PLX51107，这是一种结构独特的 BET 抑制剂，具有新颖的体外和体内药理学特性，在 CLL 临床前模型中模拟或超过 BCR 信号传导剂的功效。在此，BRD4参与核心CLL转录程序的发现为PLX51107作为CLL表观遗传疗法的临床研究以及BRD4分析在其他癌症中的应用提供了令人信服的理由。

意义：迄今为止，尚缺乏 BRD4 在 CLL 中的功能研究。通过整合基因组、功能和药理学分析，我们揭示了 BRD4 调节的核心 CLL 转录程序的存在，并提出了临床前概念验证研究，验证 BET 抑制作为 CLL 中靶向 BCR 信号传导的表观遗传学方法。癌症发现； 8(4)； 458–77。 ©2018 AACR。

这篇文章在本期特稿中重点介绍，第 17 页。第371章