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

Hannah C Beird,Feng Wang,Joseph Khoury,Marina Konopleva,P Andrew Futreal,Naveen Pemmaraju,Maliha Khan,Li Zhao,Tianyu Cai,Mansour Alfayez

doi:10.1038/s41408-019-0262-0

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.

Highlights

Blastic plasmacytoid dendritic cell neoplasm (BPDCN)is a rare, highly clinically aggressive hematologic malignancy thought to arise from proliferation of precursor plasmacytoid dendritic cells
CD123+ blasts from four BPDCN patients revealed that BPDCN is most closely related to plasmacytoid dendritic cells (pDCs), with expression of B-cell markers, such as FCRLA, IGLL1, TCL1A, and IGLL526
The features that distinguish BPDCN from acute myeloid leukemia (AML) have not been explored to great depth

Summary

Introduction

Is a rare, highly clinically aggressive hematologic malignancy thought to arise from proliferation of precursor plasmacytoid dendritic cells (pDC). Normal pDCs generate interferons during chronic viral infection, can present antigens, and have potential roles in reducing autoimmune responses. Patients are predisposed to acute leukemia transformation, despite multi-agent chemotherapy. After multiple attempts to reclassify the disease due to its protean manifestations, BPDCN was initially labeled under the umbrella of acute myeloid leukemia (AML) and associated neoplasms by the World Health Organization (WHO) in 2008. In 2016, it was re-classified by WHO under its own separate category under myeloid malignancies, highlighting its unique biology and clinical features. In the absence of standard treatment, current chemotherapy regimens borrowed from lymphoma or acute leukemia have been the preferred approach treating patients with BPDCN.

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