A Druggable TCF4-and BRD4-Dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm

作者：Ceribelli Michele; Hou Zhiying Esther; Kelly Priscilla N; Huang Da Wei; Wright George; Ganapathi Karthik; Evbuomwan Moses O; Pittaluga Stefania; Shaffer Arthur L; Marcucci Guido; Forman Stephen J; Xiao Wenming; Guha Rajarshi; Zhang Xiaohu; Ferrer Marc; Chaperot Laurence; Plumas Joel; Jaffe Elaine S; Thomas Craig J; Reizis Boris^*; Staudt Louis M^*

来源：Cancer Cell, 2016, 30(5): 764-778.

DOI：10.1016/j.ccell.2016.10.002

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETis retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.

• 出版日期2016-11-14