A Druggable TCF4- and BRD4-dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm (ATAC-Seq)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNA interference 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 expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi''s) induce BPDCN apoptosis, which was attributable to disruption of the TCF4-dependent transcriptional network and loss of BPDCN-specific super-enhancers. BETi''s retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy. Overall design: We performed ATAC-Seq to measure chromatin accessibility in normal pDCs (n=2) and primary BPDCN (n=1), together with BPDCN cell lines (Cal-1 and Gen2.2) (n=2), AML cell lines (HL-60 and MOLM-14) (n=2) and conventional myeloid DCs (n=2) as specificity controls.