Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy assumed to originate from plasmacytoid dendritic cells (pDCs), which mostly affects the skin, bone marrow, lymph nodes and sequentially other organ systems. RNA-, targeted- and exome sequencing studies have identified molecular characteristics, associated with BPDCN-pathogenesis, yet an integrative molecular assessment of BPDCN remains pending. Here, we combined paired WES/RNA-Seq with genome-wide copy-number analysis to characterize 47 BPDCN patients for mutational drivers, cytogenetic aberrations and gene-expression profiles. We identified alterations in epigenetic regulators (TET2, EP300, DNMT3A, SF3B1, EZH2) and a mutational disruption of RTK-RAS signaling (NF1, NRAS, EGFR) as drivers of BPDCN alongside deletions of tumor suppressors (CDKN2A, RB1, TP53), amplifications of oncogenes (IDH2, MET, EZH2) and recurrent fusions (MYB, ALK). The mutational landscape further provides evidence for frequent induction of PDGF signaling and extracellular matrix interactions as well as a gender specificity and a subset of MSIhigh patients. Many genes affected in BPDCN are shared with chronic myelomonocytic leukemia (CMML), emphasizing a close relationship between these entities and to a lesser extent with acute myeloid leukemia (AML). Ontological assessment of RNA-Seq data revealed two BPDCN subtypes, a typical pDC-derived subtype (C1) and a (common) cDC-enriched subtype (C2), which were then shown to exhibit distinct mutational (EP300, ARID2, NF1 mutations in typical pDC vs. DNMT3A, SRSF2 mutations in the cDC-enriched subtype) and clinical features. In summary, our hitherto most comprehensive characterization of BPDCN reveals molecular hallmarks alongside actionable vulnerabilities and highlights two novel subtypes that are molecularly and clinically distinct.

The authors have declared no competing interest.

This work was supported by generous funding by the Stefan Morsch Foundation through a project grant (NG & HW).

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 Luebeck 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Bam files from WXS and raw fastq files from RNA-Seq have been deposited in the European genome-phenome archive (EGA) under the accession number EGAS00001006166. OncoScan Array data has been deposited in Gene Expression Omnibus (GEO) under accession number GSE200113.

https://ega-archive.org

https://www.ncbi.nlm.nih.gov/geo/