Features of non-activation dendritic state and immune deficiency in blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, male-predominant hematologic malignancy with poor outcomes and with just one recently approved agent (tagraxofusp). It is characterized by the abnormal proliferation of precursor plasmacytoid dendritic cells (pDCs) with morphologic and molecular similarities to acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) in its presentation within the bone marrow and peripheral blood. To identify disease-specific molecular features of BPDCN, we profiled the bone marrow, peripheral blood, and serum samples from primary patient samples using an in-house hematologic malignancy panel ("T300" panel), transcriptome microarray, and serum multiplex immunoassays. TET2 mutations (5/8, 63%) were the most prevalent in our cohort. Using the transcriptome microarray, genes specific to pDCs (LAMP5, CCDC50) were more highly expressed in BPDCN than in AML specimens. Finally, the serum cytokine profile analysis showed significantly elevated levels of eosinophil chemoattractants eotaxin and RANTES in BPDCN as compared with AML. Along with the high levels of PTPRS and dendritic nature of the tumor cells, these findings suggest a possible pre-inflammatory context of this disease, in which BPDCN features nonactivated pDCs.

Fig. 1. Lollipop plots of TET2 mutations found in BPDCN patients tested.

Annotations are based on NM_001127208.2. The S1674fs and R1476fs mutations in BPDCN-12 were found only in the bone marrow sample that was taken 1 month after the specimen from the peripheral blood, which contained only the R1425X mutation for TET2.

Fig. 2. Differential gene expression in BPDCN (N = 6) as compared with TET2-mutated AML (AML^TET2) (N = 7).

Pie charts of the type of transcripts upregulated (a) or downregulated (b) in BPDCN as compared with AML^TET2. Coding: transcript results in a protein. Noncoding: transcript does not result in a protein. Pseudogene: transcript may not be expressed and if expressed, does not produce a functional protein. Precursor-microRNA: unprocessed, premature microRNA. Unassigned: uncharacterized transcript. Multiple_Complex: fits into multiple categories of the above. c Volcano plot showing the genes that are differentially expressed between BPDCN and AML^TET2. The genes in red (upregulated in BPDCN) and green (downregulated in BPDCN) are at fold changes −4 > x > 4, with FDR F-test adjusted P < 0.03.

Fig. 3. Serum protein levels that were significantly different between BPCN and AML.

a Eotaxin, **P < 0.01; b RANTES, *P < 0.05.