Somatic IL4R Hotspot Mutations in Primary Mediastinal Large B-cell lymphoma lead to constitutive JAK-STAT activation

Primary mediastinal large B cell lymphoma (PMBCL) is a distinct subtype of diffuse large B cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic IL4R mutations in 15 out of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8 leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain-of-function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish IL4R mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.EGA study EGAS00001002796

原发性纵隔大B细胞淋巴瘤（primary mediastinal large B cell lymphoma, PMBCL）是弥漫性大B细胞淋巴瘤的独特亚型，被认为起源于胸腺髓质B细胞。目前，该疾病分子发病机制相关的基因突变尚未被完全阐明。本研究在62例原发性纵隔大B细胞淋巴瘤原发病例中的15例（占比24.2%）以及所有被测的PMBCL来源细胞系中，发现了全新的体细胞白细胞介素4受体（IL4R）突变。其中大多数突变（11/21，占比52%）为外显子8上的热点单核苷酸变异，可导致跨膜结构域内I242N氨基酸替换。功能实验证实，该突变属于功能获得性突变，可导致JAK-STAT通路持续性激活，并上调下游细胞因子表达谱以及B细胞特异性抗原的表达。此外，在小鼠异种移植模型中表达I242N突变型IL4R，可在体内赋予细胞生长优势。JAK-STAT信号通路内的共突变模式提示，这些基因突变可通过叠加/协同效应共同参与淋巴瘤发生过程。本研究证实IL4R突变为新型驱动性变异，并为PMBCL靶向JAK-STAT信号通路的治疗策略提供了强有力的临床前依据。EGA研究编号：EGAS00001002796