Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis

Abstract

Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3− CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.

Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm

“…Our results show that genes encoding RNA splicing components are frequently mutated in BPDCN, with a collective frequency of 23%. Renosi et al [ 27 ] performed NGS targeting 68 genes on 13 cases of BPDCN and detected ZRSR2 mutations in 4 (31%) cases and SRSF2 mutations in 2 (15%) cases. Summerer et al [ 28 ] analyzed 1367 mutations in 1210 genes in 21 BPDCN cases and found mutations in SRSF2 in 7 (33%), SF3B1 in 2 (10%), U2AF1 in 2 (10%), and ZRSR2 in 2 (10%) cases.…”

Newly-Discovered Neural Features Expand the Pathobiological Knowledge of Blastic Plasmacytoid Dendritic Cell Neoplasm

“…Recently, Renosi et al documented the monoallelic deletion of NTRK genes in BPDCN. But the epigenetic control reported in the current study (i.e., acetylation of NRTK1 promoter) may overcome these deletions [ 46 ]. The neurotrophic receptors, known to promote tumor cell proliferation, differentiation, and survival, are emerging as promising therapeutic targets.…”

Single-cell Multiomics Reveals Clonal T-cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm

“…In this study, we observe increased expression of IFNA response genes in T-cells relative to Tcells in the healthy controls, initially suggesting higher levels of IFNA production by pDC-like tumor cells. However, previous research on BPDCN has shown that pDC-like tumor cells produce lower levels of IFNA relative to pDCs from healthy individuals (44,45). Further, little research has been reported describing the role of TNFA signaling in BPDCN, though studies have shown increased TNFA signaling in the plasma of patients with acute myeloid leukemia (46,47).…”