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

Publication date: 14 November 2016
Source:Cancer Cell, Volume 30, Issue 5
Author(s): Michele Ceribelli, Zhiying Esther Hou, Priscilla N. Kelly, Da Wei Huang, George Wright, Karthik Ganapathi, Moses O. Evbuomwan, Stefania Pittaluga, Arthur L. Shaffer, Guido Marcucci, Stephen J. Forman, Wenming Xiao, Rajarshi Guha, Xiaohu Zhang, Marc Ferrer, Laurence Chaperot, Joel Plumas, Elaine S. Jaffe, Craig J. Thomas, Boris Reizis, Louis M. Staudt
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.

Teaser

Ceribelli et al. use a combination of RNAi and small-molecule screening to identify TCF4 as a crucial transcriptional regulator required for maintenance of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and show that bromodomain inhibitors are potential therapeutics for BPDCN, through targeting of TCF4.


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