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

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.

母细胞性浆细胞样树突状细胞肿瘤（Blastic plasmacytoid dendritic cell neoplasm, BPDCN）是一种起源于浆细胞样树突状细胞（plasmacytoid dendritic cells, pDCs）的侵袭性且几乎无法治愈的血液系统恶性肿瘤。本研究通过RNA干扰筛选（RNA interference screening），将E盒转录因子TCF4鉴定为BPDCN致癌程序的核心调控因子。TCF4可作为BPDCN的可靠诊断标志物，其下调会导致BPDCN特异性表达程序丧失并诱导细胞凋亡。高通量药物筛选（High-throughput drug screening）结果显示，溴结构域与额外末端结构域抑制剂（bromodomain and extra-terminal domain inhibitors, BETi's）可诱导BPDCN细胞凋亡，该效应归因于TCF4依赖的转录网络被破坏以及BPDCN特异性超级增强子的丢失。BETi's可延缓BPDCN异种移植瘤的生长，为其在这一难治性恶性肿瘤中的临床评估提供了实验依据。实验整体设计：本研究采用转座酶可及性染色质测序（ATAC-Seq）检测了正常pDCs（n=2）、原发性BPDCN样本（n=1）、BPDCN细胞系（Cal-1与Gen2.2，n=2）、急性髓系白血病（Acute Myeloid Leukemia, AML）细胞系（HL-60与MOLM-14，n=2）以及常规髓系树突状细胞（n=2，作为特异性对照）的染色质可及性。