Genetics and Epigenetics in Neoplasms with Plasmacytoid Dendritic Cells

SIMPLE SUMMARY: Differential diagnosis between Blastic pDC Neoplasm (BPDCN) and Acute Myeloid Leukemia with pDC expansion (pDC-AML) is particularly challenging, and genomic features can help in diagnosis. This review aims at clarifying recent data on genomics features because the past five years have generated a large amount of original data regarding pDC neoplasms. The genetic landscape of BPDCN is now well-defined, with important updates concerning MYC/MYC rearrangements, but also epigenetic defects and novel concepts in oncogenic and immune pathways. Concerning pDC-AML, they now appear to exhibit an original mutation landscape, especially with RUNX1 mutations, which is of interest for diagnostic criteria and for therapeutic purposes. We highlight here these two different profiles, which contribute to differential diagnosis between BPDCN and pDC-AML. This point is particularly important for the study of different therapeutic strategies between BPDCN and AML. ABSTRACT: Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective.