Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis [patients]

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. Overall design: RNA sequencing of 11 BPDCNs and 4 normal pDC samples

母细胞性浆细胞样树突状细胞肿瘤（Blastic plasmacytoid dendritic cell neoplasm, BPDCN）是一类源于浆细胞样树突状细胞（plasmacytoid dendritic cells, pDCs）的侵袭性白血病。BPDCN的男性发病率至少为女性的3倍，但这种性别偏倚的成因至今未明。本研究通过对原发性BPDCN开展基因组学分析，并构建疾病相关突变模型，揭示了RNA剪接的获得性改变经由Toll样受体（Toll-like receptors）介导异常的pDC发育与炎症应答。编码剪接因子的X染色体基因ZRSR2的功能丧失性突变在BPDCN中富集，且几乎所有此类突变均发生于男性患者体内。ZRSR2突变可损害炎症刺激后pDC的活化与细胞凋亡，该现象与内含子滞留以及无法上调转录因子IRF7的表达密切相关。在体内实验中，BPDCN相关突变可促进pDC扩增，并使细胞呈现活化水平降低的分子特征。上述数据支持如下模型：造血祖细胞中存在的男性偏向性突变可改变pDC功能，赋予其抗凋亡特性，进而可能损害免疫功能并增加白血病转化风险。实验整体设计：对11例BPDCN样本与4例正常pDC样本进行RNA测序。