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

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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

Edité par CCSD ; Elsevier -

International audience. 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. Published by Elsevier Inc.

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