Genome-wide DNA methylation-analysis delineates blastic plasmacytoid dendritic cell neoplasm from related entities and identifies distinct molecular features

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid/common dendritic cells (pDCs/cDCs) 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 (n=54) and RNA-seq (n=54) as well as ATAC-seq on selected cases (n=4). We determine the BPDCN DNA methylation profile and thereby identify a reliable means to discriminate BPDCN from AML, CMML and T-ALL. DNA methylation profiling characterizes disruption of oncogenic pathways whilst unraveling the proliferative history as well as the prognostically relevant composition of the tumor microenvironment. Beyond the two recently established BPDCN subtypes (C1/C2), we identified a transcriptional reliance on JAK/STAT and NFκB-signaling in atypical C2 versus C1-BPDCN cases through RNA-sequencing. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by generous funding by the Stefan Morsch Foundation through a project grant (NG & HW). X.C. is supported by Swedish Research Council (2022-00658) and Swedish Cancer Foundation (21 1449Pj and 22 0491). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This retrospective study was approved by the ethics committee of the University of Luebeck (reference-no 18-311) and conducted in accordance with the declaration of Helsinki. Patients at the Reference center for Hematopathology have provided written informed consent regarding routine diagnostic and academic assessment, including genomic studies of their biopsy specimen alongside transfer of their clinical data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes