BET Inhibitors Target Blastic Plasmacytoid Dendritic Cell Neoplasms

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy that arises from plasmacytoid dendritic cells (pDC), innate immune cells whose lineage commitment is controlled by the E-box transcription factor TCF4. BPDCN has a poor survival rate and most patients develop drug-resistant disease. Thus, a better understanding of the molecular pathways underlying BPDCN may lead to new targeted therapies. Ceribelli and colleagues performed a loss-of-function RNAi screen and identified TCF4 as an essential regulator required for BPDCN cell survival. Chromatin immunoprecipitation sequencing combined with gene expression profiling in BPDCN cells revealed 399 genes upregulated by TCF4 and 630 genes downregulated by TCF4, most of which were bound by TCF4 at E-box motifs in the promoter or gene body. Genes upregulated by TCF4 included genes required for pDC development and function, and oncogenes including MYC, BCL2, TCL1A, and TCL1B. The pDC genes were more highly expressed in normal pDCs compared with BPDCNs, whereas the oncogenes were more highly expressed in BPDCNs. Strong homogenous expression of TCF4 was observed in 24 out of 28 BPDCN tumors, suggesting the possibility of using TCF4 expression as a diagnostic marker of BPDCN. A high-throughput drug screen testing 1,910 small molecules found that BPDCN cells were specifically sensitive to three different bromodomain and extra-terminal domain (BET) inhibitors, and BET inhibition reduced the growth of BPDCN xenografts. The BET protein BRD4 was also a top hit in the siRNA screen, indicating it may be the target of BET inhibition. Moreover, BET inhibition targeted the TCF4 transcriptional network, reducing expression of TCF4 and its target genes and decreasing TCF4 occupancy of target genes. Further, BRD4 occupancy defined BPDCN superenhancers, one of which regulated TCF4 expression and was bound by TCF4 itself. Together, these data indicate that a TCF4/BRD4 transcriptional network underlies BPDCN and suggest that BET inhibitors may potentially be effective in patients with BPDCN.

Ceribelli M, Hou ZE, Kelly PN, Huang DW, Wright G, Ganapathi K, et al. A druggable TCF4- and BRD4-dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell 2016;30:764–78.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.