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

Abstract

SUMMARY 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 gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi’s) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETi’s retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

“…ATAC-Seq and ChIP-Seq analysis of transformed human pDC cell lines identified multiple regulatory elements 5′ of TCF4 , which collectively comprised a super-enhancer (Ceribelli et al, 2016). Similarly, ATAC-Seq on normal murine cells (Fig.…”

“…In transformed human pDC lines, the expression of TCF4 and activity of all its regulatory regions were dependent on bromodomain and extraterminal (BET) domain-containing proteins (Ceribelli et al, 2016). BET proteins comprise a family of transcriptional cofactors that are particularly important for the activity of super-enhancers, and their inhibition by drugs such as JQ1 potently inhibits cell growth (Delmore et al, 2011).…”

“…Thus, distal 5′ and 3′ regulatory elements appear to drive TCF4 expression, and their combinations with the respective promoters yield broader (for TCF4 S ) or pDC-specific (for TCF4 L ) expression patterns. In cultured human pDC lymphoma cell lines, the activity of all distal regulatory elements of TCF4 is controlled by BET domain proteins and is inhibited by BET inhibitor JQ1 (Ceribelli et al, 2016). Accordingly, Tcf4 expression during pDC differentiation was also inhibited by JQ1, extending this mechanism to normal DC development.…”

“…Cells were stained for 1 hr at room temperature with control rabbit IgG or with a rabbit mAb to TCF4 (Ceribelli et al, 2016). The cells were then washed, incubated with PE-conjugated anti-rabbit IgG (Jackson Immunoresearch) and analyzed by flow cytometry.…”

A Case of Blastic Plasmacytoid Dendritic Cell Neoplasm Extensively Studied by Flow Cytometry and Immunohistochemistry

“…In fact, available information derived from retrospective case reports and single-institution experiences suggests that adults may benefit from allogeneic HSCT in first CR, achieving long-term survival with both myeloablative and reduced intensity conditioning regimens [17, 29–31]. Moreover, novel potential therapeutic targets have been identified, such as BCL-2, an antiapoptotic protein commonly overexpressed in BPDCN, as in our case [8, 16, 32, 33]. The chance to find effective targeted therapies furtherly strengthens the need for complete characterization of this neoplasm.…”