Abstract
INTRODUCTION:
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic neoplasm with poor outcomes and limited therapeutic options. BPDCN pathogenesis is not clear, given that half of patients present with skin tumors without overt bone marrow involvement ("skin-only" disease). Most patients with "skin-only" BPDCN will eventually develop disease progression with bone marrow infiltration. Accordingly, a model of BPDCN pathogenesis has been proposed wherein malignant transformation of a plasmacytoid dendritic cell first occurs in the skin and is followed by dissemination to the bone marrow. Formal evidence to support this model is lacking.
METHODS:
To study the developmental ontogeny of BPDCN, we performed DNA sequencing of diagnostic bone marrow and skin biopsies from 10 patients. Four patients had "skin-only" disease with negative marrow assessments by histology and flow cytometry (Fig 1A-B). Two patients had skin tumors with limited marrow involvement (≤10% of the cellularity) and 4 patients had skin tumors with extensive concurrent marrow involvement. Six of ten patients had marrow sequencing performed serially before and after therapy. Exon capture and amplicon-based targeted sequencing assays covering recurrently mutated genes in blood cancers were used. Whole exome sequencing (WES) was also performed on germline DNA, "uninvolved" marrow, and a skin tumor from one patient with "skin-only" BPDCN.
RESULTS:
All patients with "skin-only" disease and negative bone marrow assessment at diagnosis harbored high variant allele frequency (VAF) mutations in the bone marrow, consistent with clonal hematopoiesis (Fig 1C). Two patients with cutaneous disease and only limited marrow involvement also demonstrated multiple high VAF mutations in the marrow that exceeded the degree of BPDCN tumor involvement. Mutations observed in these patients' bone marrows included known pathogenic variants in genes recurrently mutated in BPDCN and other blood cancers, including ASXL1 (4/6 cases; 45-71% VAF), TET2 (4/6; 31-45% VAF), SF3B1 (1/6; 22% VAF), ZRSR2 (1/6; 86% VAF), CUX1 (1/6; 88% VAF), and EZH2 (1/6; 79% VAF).
Post-therapy analysis also suggested underlying clonal hematopoiesis in BPDCN. In a patient with 10% bone marrow involvement by tumor at diagnosis, persistent high VAF TET2 and ZRSR2 mutations were noted post-therapy despite a reduction in tumor burden to <1% of the cellularity (Fig 1D, patient 5). Similarly, 2 patients with more extensive marrow involvement at diagnosis (>30% of the cellularity) showed persistence of pathogenic mutations in JAK2, SRSF2, and GNB1 post-therapy despite a reduction in the marrow tumor burden to <1% of the cellularity (Fig 1D, patients 4 and 8).
Most marrow mutations were also detected in paired biopsies of skin tumors, suggesting clonal progression from a pre-malignant marrow precursor. To further validate the clonal relationship between these anatomic compartments in BPDCN, we performed WES in one patient with "skin-only" disease who showed identical ASXL1 and TET2 mutations in the marrow and skin at diagnosis. Interestingly, by WES, 87% of all somatic single nucleotide variants (SNVs) were unique to the skin tumor, 11% of SNVs were unique to the bone marrow, and only 2% were shared between both anatomic sites (Fig 1E). This supports a model of branching pre-malignant evolution in the marrow, with one sub-clone seeding the skin and acquiring additional mutations during malignant transformation.
CONCLUSION:
Clonal hematopoiesis is a defining feature of BPDCN. High VAF mutations in the bone marrow of BPDCN patients without overt tumor involvement likely reflects extensive pre-malignant clonality rather than infiltration by tumor cells arising in the periphery. In contrast to clonal hematopoiesis of indeterminant potential (CHIP), which usually has a single gene mutated at low VAF, uninvolved marrow in BPDCN often harbors multiple mutations at high clonal burden. These data suggest that the earliest events in BPDCN pathogenesis occur in hematopoietic progenitor cells, which then seed peripheral sites during complete malignant transformation. These findings also raise concern about the use of morphologically "normal" stem cells for autologous transplantation in patients with BPDCN.
Disclosures
Griffin: Moderna Therapeutics: Consultancy. Lane:N-of-one: Consultancy; Stemline Therapeutics: Research Funding.
PERBANDINGAN REGRESI ZERO INFLATED POISSON (ZIP) DAN REGRESI ZERO INFLATED NEGATIVE BINOMIAL (ZINB) PADA DATA OVERDISPERSION (Studi Kasus: Angka Kematian Ibu di Provinsi Bali)
