Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignancy previously known as blastic natural killer cell lymphoma, CD4+CD56+ hematodermic neoplasm, or agranular CD4+ NK cell leukemia. BPDCN has recently been classified as the malignant counterpart of plasmacytoid dendritic cells (pDCs), the most common dendritic cell subset in peripheral blood. Clinical outcomes in BPDCN are poor, with median survival of less than 12 months. The pathogenesis and genetic changes associated with pDC transformation are largely unknown, and the optimal treatment for this disease is unclear. Loss of the CDKN2A locus on 9p21 is the most common copy number alteration, and the sole targeted sequencing effort reported to date focused only on somatic mutations in TP53 and TET2 (Jardin et al. Br J Haem 2011). The goal of this study was to characterize the genetics of BPDCN by next-generation sequencing of all exons of 219 genes known to be recurrently mutated in hematologic malignancies. We sequenced a discovery cohort of seven adult patients with BPDCN, and confirmed the somatic status of single nucleotide variants (SNVs) and insertion-deletions (InDels) not present in dbSNP using paired germline tissue where available. All cases met World Health Organization criteria for pathological diagnosis of BPDCN. We confirmed the presence of TET2 (4 of 7 patients) and TP53 (1 of 7) mutations in BPDCN, and noted that the overall mutational spectrum was overlapping with previously sequenced hematologic neoplasms. Specifically, we observed mutations in ASXL1 (in 2 patients: K586* and an InDel causing a frameshift at S795), IDH2 (R140Q), KRAS (G13D), ABL1 (T315I), ARID1A (R1721*), GNA13 (E313*), U2AF1 (Q157L), and SRSF2 (P95L) that have been reported in myeloid and mature B cell neoplasms. Also of interest was an IRF8 R404W mutation; IRF8 is a transcription factor that drives pDC development and germline loss of IRF8 in humans is associated with dendritic cell deficiency. The most striking finding was the presence of premature stop, frame shift, and splice site mutations in the splicing factor ZRSR2 on chromosome Xp22.1 in 4 of 7 (57.1%) BPDCNs. ZRSR2 mutations were present in 71-84% of sequence reads at their respective locations, consistent with homo/hemizygous alterations in a dominant clone. Xenografting of one BPDCN that harbored a ZRSR2 premature stop mutation resulted in leukemia engraftment that retained the ZRSR2 mutation. From a validation cohort of 32 additional adult and pediatric BPDCNs, ZRSR2 mutations were present in 11 cases, for a total of 15 of 39 (38.5%) patients. Ten of 15 mutations were premature stop, frame shift, or splice site, while the remaining were missense variants. ZRSR2 is recurrently mutated in MDS and AML but at a much lower frequency (1-5%), and ZRSR2 mutations have not been described as characteristic of any other malignancy. Thus, ZRSR2 mutations are approximately 10-fold more prevalent among BPDCNs as compared to MDS or AML, indicating a unique association between BDPCN and ZRSR2 mutation. BPDCN is predominantly a disease of the male sex, both in previous studies and in our cohort (28 males among 36 patients, 77.8%). In a prior report (Yoshida et al. Nature 2012), 12 of 12 cases of MDS with ZRSR2 nonsense and frame shift mutations were male. All 10 cases of BPDCN with ZRSR2 nonsense, frame shift, and splice site mutations in our cohort were male (P=0.076 by two-sided Fisher’s exact test). Thus, we hypothesize that BPDCN may be more common in males because of a gene dosage effect related to the chr.X location of ZRSR2. There was also a trend toward an association between ZRSR2 loss-of-function mutation and age ≥65 (P=0.068). There was no statistically significant difference in overall survival between patients with and without mutations in ZRSR2, although we were limited by the small cohort size and the heterogeneity of therapies received. We conclude that loss of ZRSR2 function is specifically associated with pDC transformation and leukemogenesis, as well as male sex and older age. Further studies to confirm these findings in additional cohorts and define the mechanism linking ZRSR2 mutation with BPDCN are underway. Disclosures: DeAngelo: Ariad, Novartis, BMS: Consultancy. Neuberg:Synta Pharmaceuticals: Trust owns stock; I am a Trustee Other.

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