Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients supplemented by WES and RNA-seq as well as ATAC-seq on selected cases. We determined the BPDCN DNA methylation profile and observed a dramatic loss of DNA methylation during malignant transformation from early and mature DCs towards BPDCN. DNA methylation profiles further differentiate between BPDCN, AML, CMML, and T-ALL exhibiting the most striking global demethylation, mitotic stress, and merely localized DNA hypermethylation in BPDCN resulting in pronounced inactivation of tumor suppressor genes by comparison. DNA methylation-based analysis of the tumor microenvironment by MethylCIBERSORT yielded two, prognostically relevant clusters (IC1 and IC2) with specific cellular composition and mutational spectra. Further, the transcriptional subgroups of BPDCN (C1 and C2) differ by DNA methylation signatures in interleukin/inflammatory signaling genes but also by higher transcription factor activity of JAK-STAT and NFkB signaling in C2 in contrast to an EZH2 dependence in C1-BPDCN. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications.

母细胞性浆细胞样树突状细胞肿瘤（BPDCN）是一种罕见的侵袭性恶性肿瘤，起源于浆细胞样树突状细胞（pDC），主要具有皮肤趋向性，随后播散至骨髓和其他器官。我们在 45 名 BPDCN 患者的扩展队列中对肿瘤甲基化组进行了全基因组分析，并在选定的病例上辅以 WES 和 RNA-seq 以及 ATAC-seq。我们确定了 BPDCN DNA 甲基化谱，并观察到在从早期和成熟 DC 向 BPDCN 恶性转化过程中 DNA 甲基化急剧丧失。 DNA 甲基化谱进一步区分了 BPDCN、AML、CMML 和 T-ALL，显示出最显着的整体去甲基化、有丝分裂应激和 BPDCN 中仅局部 DNA 高甲基化，从而导致肿瘤抑制基因明显失活。 MmethylCIBERSORT 对肿瘤微环境进行基于 DNA 甲基化的分析，产生了两个与预后相关的簇（IC1 和 IC2），具有特定的细胞组成和突变谱。此外，BPDCN 的转录亚组（C1 和 C2）的不同之处在于白细胞介素/炎症信号传导基因中的 DNA 甲基化特征，而且 C2 中 JAK-STAT 和 NFkB 信号传导的转录因子活性较高，与 C1-BPDCN 中的 EZH2 依赖性相反。我们对 BPDCN 的综合表征提供了新颖的分子见解和潜在的诊断应用。