A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm

We combined loss-of-function RNA interference screening and a high-throughput drug toxicity screening to define novel therapeutic targets in blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy for which no curative therapy exists. The E-box transcription factor TCF4 emerged as the master transcriptional regulator of the BPDCN oncogenic program, a finding that can be exploited for the accurate molecular diagnosis of BPDCN. Genetic interference with the TCF4-dependent network induced a rewiring of BPDCN gene expression, resulting in apoptosis. Treatment of BPDCN lines with bromodomain and extra-terminal domain inhibitors (BETi's) down regulated TCF4 and its target gene network, inducing apoptosis both in vitro and retarding growth of BPDCN xenografts in vivo, supporting the clinical evaluation of BETi's in this lethal cancer. For shRNA gene expression profiling, Cal-1 and Gen2.2 cells were infected with either Ctrl or TCF4 shRNAs. Following puromycin selection, shRNA expression was induced for 24 hours and 48 hours in Cal-1 cells (n=4), and for 12 hours and 24 hours in Gen2.2 cells (n=4). For JQ1 gene expression profiling, Cal-1 (n=4) and Gen2.2 (n=4) cells were treated with either DMSO or 100 nM JQ1 for 1 hour, 3 hours, 8 hours and 24 hours.