pDCs develop from a common myeloid-dendritic progenitor that is found in the bone marrow. After maturation, they circulate as 0.5% to 1% of peripheral blood mononuclear cells and are also found in secondary lymphoid organs such as lymph nodes, tonsil, and spleen. They are not frequently detected in the skin under normal circum stances. It is not clear if a specific stage of hematopoietic stem cells, pDC progenitors, or mature pDCs is the target for transformation to BPDCN. Similarly, we do not know if the initial transformation event takes place in bone marrow, peripheral blood, lymphoid organs, or skin. Investigation of these questions regarding the developmental ontogeny of BPDCN is an active area of ongoing research.
At least 50% of BPDCNs have an abnormal karyotype by cyto genetic analysis. However, there is no consistent translocation, mutation, deletion, or amplification event that defines all cases of BPDCN. Recurrent copy loss of specific chromosomes is a common feature, including minimal deleted regions that include known tumor suppressor genes, many of which are cell cycle regulators: 7p12 (IKZF1), 9p21 (CDKN2A/CDKN2B), 12p13 (CDKN1B), 13q11 (LATS2), 13q13 (RB1), and 17p (TP53). Rearrangements of 8q24 involving the MYC gene were reported in 40% of cases in a Japanese BPDCN population, with at least half only detectable using fluorescence in situ hybridization (FISH). In that series, MYC rearrange ment was associated with poorer overall survival (OS) in univariate analysis. In a subset, the translocation t(6;8)(p21;q24) positions an enhancer region of the dendritic lineage-specific gene RUNX2 on 6p21 upstream of the MYC gene, driving its high expression. Despite these findings, in our center’s BPDCN population, we have not seen these high rates of MYC rearrangement, possibly related to differences in North American and Japanese populations. Therefore, we do not routinely perform FISH for MYC abnormalities. Pediatric BPDCN may also be distinct cytogenetically as it is enriched compared to adults for translocations involving the MYB locus and does not have other adult-type BPDCN-associated gene mutations.
Somatic mutations acquired in BPDCN cells overlap with the genes mutated in myeloid malignancies, supporting a similar cell of origin. The affected genes are particularly overlapping with those observed in patients with MDS and CMML, and include TET2, ASXL1, RNA splicing factors (e.g., SF3B1, SRSF2, U2AF1, ZRSR2), TP53, and others mutated in AML, including IDH1, IDH2, KRAS, and NRAS. Some series identified mutations in transcription factors that may be involved in pDC lineage-related transformation, including IKZF1, IKZF2, IKZF3, and ZEB2. Unlike AML, mutations in DNMT3A, FLT3, and NPM1 are not common.
Gene expression profiling, including by single cell RNA sequencing, support that the closest normal counterpart of BPDCN is the pDC or its immediate precursors. BPDCNs also express high levels of the antiapoptotic gene BCL2 and have upregulated expression of nuclear factor kappa B (NF-κB) gene signatures, which may suggest targets for therapy.
