BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.
BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.
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DOI：
10.1158/2159-8290.cd-17-0902
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发表时间：
2018-04
期刊：
影响因子：
28.2
通讯作者：
Lapalombella R
中科院分区：
文献类型：
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作者：
Ozer HG;El-Gamal D;Powell B;Hing ZA;Blachly JS;Harrington B;Mitchell S;Grieselhuber NR;Williams K;Lai TH;Alinari L;Baiocchi RA;Brinton L;Baskin E;Cannon M;Beaver L;Goettl VM;Lucas DM;Woyach JA;Sampath D;Lehman AM;Yu L;Zhang J;Ma Y;Zhang Y;Spevak W;Shi S;Severson P;Shellooe R;Carias H;Tsang G;Dong K;Ewing T;Marimuthu A;Tantoy C;Walters J;Sanftner L;Rezaei H;Nespi M;Matusow B;Habets G;Ibrahim P;Zhang C;Mathé EA;Bollag G;Byrd JC;Lapalombella R
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。在这里，我们利用BRD4图谱来识别慢性淋巴细胞白血病(CLL)发病机制中的关键途径。BRD4在CLL中高表达，并且在CLL中表达上调或重新表达的基因附近富含BRD4，已知其在疾病发生发展中的作用。这些基因，包括BCR信号通路的关键成员，为这种治疗方法提供了理论基础，以确定替代类型癌症的新靶点。此外，我们描述了PLX51107，一种结构独特的BET抑制剂，具有新的体外和体内药理特性，在CLL的临床前模型中模拟或超过BCR信号剂的疗效。在这里，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和BRD4在其他癌症中的应用提供了令人信服的理论基础。
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 over-expressed in CLL and is enriched proximal to genes up-regulated or de novo expressed in CLL with known function in disease pathogenesis and progression. These genes, including key members of the BCR signaling pathway, provide 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 pre-clinical 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.