Blastic plasmacytoid dendritic cell neoplasm: ontogeny, immunophenotype, genetics and epigenetics, immune dysregulation, skin tropism and therapeutic implications.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, highly aggressive hematologic malignancy characterized by frequent cutaneous involvement, rapid systemic dissemination, and poor clinical outcomes. Although initially misclassified due to overlapping morphologic and immunophenotypic features with other acute leukemias, lymphomas, and NK-cell neoplasms, BPDCN is now recognized as a distinct hematologic malignancy. Advances in immunophenotyping, transcriptional profiling, and genomic analysis have clarified the cellular origin of BPDCN and revealed that the disease commonly arises from hematopoietic stem or progenitor cells harboring clonal hematopoiesis (CH)-associated mutations. Subsequent transcriptionally regulated lineage commitment to the pDC program and acquisition of cooperating genetic and epigenetic lesions drive malignant transformation. Recurrent alterations affecting epigenetic regulators, RNA splicing factors, transcriptional networks, and chromatin organization disrupt interferon signaling, promote immune evasion, and stabilize malignant identity. A defining clinical and biological feature of BPDCN is its marked skin tropism, mediated by aberrant expression of adhesion molecules and chemokine receptors and shaped by ultraviolet light-associated mutational selection within the cutaneous microenvironment. This review integrates the current knowledge of BPDCN ontogeny, morphologic and immunophenotypic features, genetic and epigenetic architecture, immune dysregulation, and mechanisms of skin tropism into a proposed unified model of leukemogenesis with implications for diagnosis, prognostication, and biology-driven therapeutic strategies.