Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy involving blastic plasmacytoid dendritic cells infiltration in various tissues. Initially classified as an acute myeloid leukemia subtype in the 2008 World Health Organization (WHO) classification, it became a distinct entity under histiocytic and dendritic cell neoplasms in the 2016 update.1-3 Despite recent advances in CD123-targeted therapies that include SL-401 (frontline/salvage),4, 5 CD123 antibody-drug conjugates (e.g. IMGN-632), CD123 chimeric antigen receptor T-cell therapies (e.g. MB-102) and combinations of SL-401 with other therapeutic agents like venetoclax and hypomethylating drugs. However, cytotoxic chemotherapy followed by transplantation remains vital, particularly in resource-limited settings.6 Understanding BPDCN's incidence, behaviour and initial treatment is challenging due to its rarity, with whole genome sequencing (WGS) data from Asian populations especially scarce.7-9 This study received ethics approval in two stages: first for the KBPDCN study, focused on clinical data analysis, and then for the KBPDCN-GENE study, focused on genetic analysis. Conducted by 20 institutions in the Consortium for Improving Survival of Lymphoma (CISL) in South Korea, the study retrospectively identified 39 cases of BPDCN, diagnosed between April 2002 and October 2020. Afterwards, pathological slides were reviewed by two pathologists according to the 2022 WHO criteria (G.-S.P. and M.G.P.). The key diagnostic markers included CD123, CD4, CD56 and other plasmacytoid dendritic cell markers. Of the 35 confirmed BPDCN cases, 13 underwent WGS using genomic DNA from formalin-fixed paraffin-embedded tumour blocks. Sequencing was conducted on an Illumina NovaSeq 6000, yielding approximately 600 million reads per sample with a 151-bp paired-end configuration (Figure S1). Detailed information on the clinical and WGS analysis was listed in the Supporting Information. Among the 35 patients included in this study, the median age at diagnosis was 56 years. Immunophenotypically, 82% of cases exhibited CD123+, CD4+ and CD56+ (Tables S1 and S2). On average, three cases were diagnosed annually with BPDCN (Figure S2). Despite a high response rate after leukaemia-like regimens, there were frequent relapses after chemotherapies (Figure S3; Table S3). After a median follow-up of 29 months, the median overall survival (OS) was 23 months. Allogeneic stem cell transplantation (allo-SCT) significantly improved outcomes, with a median OS of 54 months for those receiving allo-SCT compared to 8 months for those who did not (Figure S4; Table S4). Multivariate analysis identified age ≥55 years, poor performance status (Eastern Clinical Oncology Group performance status [ECOG PS] ≥2), liver involvement and lymphoma-like chemotherapy as significant prognostic factors affecting poor OS (Table 1). The identification of these factors aligns with previous multicentre studies, which suggest that older patients and those with poorer performance statuses are less tolerant of intensive chemotherapy treatments. Additionally, previous studies have identified disseminated disease, which may include cutaneous and extranodal disease, as indicators of poor prognosis.6, 10, 11 However, the specific emphasis on liver involvement in this study, despite the small number of patients to make a solid conclusion, highlights a unique and critical aspect of BPDCN prognosis not extensively documented before. This study, the first population-based WGS analysis of Asian BPDCN patients, examined 13 of 35 cases, identifying 103 mutations, including 72 SNVs, 37 indels and 48 CNAs (Tables S5 and S6). Excluding intronic/synonymous variants, TET2, RUNX1 and KMT2D were most frequently mutated. Notably, multi-hit TET2 mutations (missense and frameshift) were found in two cases (Figure S5). Pathway analysis highlighted the protein kinase pathway with significant CNAs in ABL1, CDKN2A/B and JAK2 (Figure 1). Methylation/chromatin remodelling genes, including TET2 and the MLL gene family, were also mutated, including missense, insertion and copy number deletion. The recurrence of TET2 mutations in BPDCN aligns with previous research, underscoring its pivotal role in the pathogenesis of this malignancy.8, 12, 13 Moreover, mutations were frequently observed in the KMT2 (MLL) gene family, which includes histone methyltransferases that are crucial for chromatin configuration and gene expression. These genetic insights into TET2 and KMT2 mutations highlight the complex interplay of epigenetic regulators in BPDCN. BPDCN patients exhibited large-scale chromosomal CNAs, with losses occurring more frequently than gains (Figures S6 and S7). Notably, four patients experienced copy number losses in the 9p21.3-1 region, which includes CDKN2A and CDKN2B, that are vital for cell cycle regulation. The absence or reduced expression of these tumour suppressor genes can lead to disrupted cell cycle control, contributing significantly to the disease's pathogenesis. Our study detected 19 in-frame translocations, accounting for 62% of the cohort (Figure S8; Table S7). Additionally, we noted recurrent rearrangements: The most common was DRG2::NRCAM, found in 31% of patients, followed by NRP1::ANP32E in 23%. These findings suggest key areas of genomic instability that may contribute to the pathophysiology of the disease. Additionally, many genes involved in structural variations, such as gene translocations, are involved in signalling pathways related to transmembrane receptor protein tyrosine kinases. However, these translocations are novel and have not been previously associated with specific diseases, which poses challenges in fully understanding their biological significance and their role in haematological malignancies. Moreover, we were unable to validate or perform the functional characterization of these novel fusions due to the limited availability of samples, which should be addressed in future studies. The discovery of a translocation involving NRP1 and ANP32E in this study introduces new avenues for research. NRP1, also known as CD304, is expressed on BPDCN cells and is linked to cell migration, suggesting its potential as both a therapeutic target and a monitoring tool for BPDCN progression and treatment response. In conclusion, this study marks a significant milestone as the first comprehensive examination of the epidemiology and clinico-genetic features of BPDCN in the Korean population. Through WGS, the research has identified a prevalent occurrence of DNA methylation gene mutations specific to Asian patients with BPDCN as well as novel genetic translocations, despite the limited number of patients analysed. Furthermore, the study highlights critical prognostic factors that adversely affect overall survival, including older age, poor performance status, liver involvement and the use of lymphoma-like induction chemotherapy. These insights not only deepen the understanding of BPDCN's unique characteristics but also enable a more tailored approach in treating and studying BPDCN in this particular ethnic population that could inform global perspectives on the disease. Ji Hyun Lee, Seok Jin Kim and Saeam Shin designed the study. Ji Hyun Lee, Sung-Yong Oh, Sung-Soo Yoon, Youngil Koh, Ja Min Byun, Dok Hyun Yoon, Jae-Cheol Jo, Deok-Hwan Yang, Seo-Yeon Ahn, Hyeon Seok Eom, Hyewon Lee, Ji Yun Lee, Jong Ho Won, Ho-Young Yhim, Ho Sup Lee, Won Seog Kim and Seok Jin Kim enrolled patients and collected data. Taek Gyu Lee, Saeam Shin, Seung-Tae Lee and Namhee Kim performed genetic testing and analysed data. Min Gyoung Pak and Gyeong-Sin Park reviewed pathological slides. Ji Hyun Lee, Taek Gyu Lee, Saeam Shin and Seok Jin Kim analysed the data. Ji Hyun Lee, Taek Gyu Lee, Min Gyoung Pak, Saeam Shin and Seok Jin Kim wrote the paper. All the authors revised the paper. This work was supported by Dong-A University research fund and Korea Health Industry Development Institute (KHIDI) (Grant reference number: HI22C0999). The authors declare no competing financial interests. This study received approval from the ethics committee of each participating centre in two stages: first for the KBPDCN (Blastic plasmacytoid dendritic cell neoplasm in the Korean population) study, focusing on clinical data analysis (IRB No. SMC 2019-02-035), and subsequently for the KBPDCN-GENE study, focusing on genetic analysis in available cases (IRB No. SMC 2020-03-174), in accordance with the Declaration of Helsinki. Data will be provided upon direct request to the authors. For original data requests, contact [email protected] and [email protected]. Data S1. 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