SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities
作者信息Benedikt Pelzer, Cem Meydan, Isaac M Spiegel, Ioannis Karagiannidis, Min Xia, Matt Teater, Emma M Welter, Zowie E Searcy, Laura K Hilton, Darko Barisic, Amos Fong, Pengyan Fa, Shenon Sethi, Irem S Isgor, Jessie J Fielding, Alireza Karbalayghareh, Colin S Burdette, Sravya Tumuluru, Sonia M Debek, Sunjae Lee, Ramon Massoni-Badosa, Ceyda Durmaz, Eralda Salataj, Prasath Pararajalingam, Zhengming Chen, Richard J Pelzl, Sanket Shah, Martin A Rivas, Kenneth B Hoehn, Coraline Mlynarczyk, Hannah M Isles, Xiang Wang, Ahmet Dogan, Kojo S J Elenitoba-Johnson, David W Scott, Kostiantyn Dreval, Ryan D Morin, Christina S Leslie, Rishi Puri, Jacob B Geri, Christopher R Chin, Amy Chadburn, Christopher E Mason, Hans Christian Reinhardt, Montserrat C Anguera, Wendy Béguelin, Leandro Venturutti, Ari M Melnick
弥漫大B细胞淋巴瘤（DLBCL）在遗传和表型上具有异质性，这使其诊断和治疗面临挑战。现有模型认为DLBCL源于参与适应性免疫反应的滤泡B细胞。通过对BN2-DLBCL亚型中SPEN和NOTCH2共现截短突变的研究，我们的数据提示了一种先前未被识别的滤泡外分化轨迹。利用动物模型和人类样本，我们发现这一协同突变轴支持具有边缘区、记忆B细胞特征以及一种独特的自身免疫性B细胞样状态的推定克隆前体细胞的扩增。该分化轨迹与性别偏向性预后相关：在我们的队列中，女性患者和小鼠的生存期较男性更短。进一步分析将这种差异与X染色体连锁的Toll样受体信号通路表达和功能增强联系起来。我们在临床前模型中证明，IRAK抑制代表了一种潜在的性别特异性治疗策略。这些发现支持BN2-DLBCL具有独特的发育起源，并识别出一个存在可操作靶点的高风险女性群体，为精准治疗提供了方向。
