The Role of SOCS1 Mutations in the Pathogenesis of Hodgkin Lymphomas and Diffuse Large B Cell Lymphomas

SOCS 1在生殖中心B细胞来源的淋巴瘤中突变，在不同淋巴瘤亚组之间的患病率和突变模式存在显著差异。使用灵敏的测序技术，适合于富含GC的SOCS 1基因座的分析，我们检测到SOCS 1基因突变超过80%的小儿霍奇金淋巴瘤（HL）和约40%的弥漫性大B细胞淋巴瘤（DLBCL）。此外，最近的研究表明，SOCS 1在离体培养的生发中心B细胞中的失活导致这些细胞的永生化。因此，SOCS 1失活可能是这些淋巴瘤发病机制中重要的和潜在的初始事件。我们的目的是对SOCS 1突变在年轻和成年HL患者以及DLBCL发病机制中的作用进行全面的研究。我们计划：1）对儿童和成人经典HL和DLBCL中SOCS 1突变的患病率和模式进行比较研究，使用适用于富含GC的SOCS 1基因座的灵敏测序技术分析大量样本，2）使用最近开发的算法在所有观察到的SOCS 1变体中鉴定功能相关的SOCS 1突变，3）分析原代培养的生发中心B细胞中SOCS 1失活对增殖、凋亡、基因组稳定性、进一步突变的获得、转录组的变化和信号通路的激活的影响，4）研究功能相关的SOCS 1突变在不同淋巴瘤细胞系和培养的具有不同SOCS 1基因型的原代人生殖中心B细胞中的竞争性ORF筛选中的作用，5）在细胞系和人生殖中心B细胞中共表达SOCS 1同种型和其他基因的潜在致癌变体以鉴定协同效应，6）在DLBCL细胞系中进行全基因组CRISPR/Cas9筛选以鉴定协同效应。这些互补的结构和功能基因组学方法的应用将揭示重要的新的方面的发病机制的生殖中心B细胞来源的淋巴瘤。

SOCS1 is mutated in germinal center B cell derived lymphomas with significant differences in prevalence and mutation pattern between diverse lymphoma subgroups. Using sensitive sequencing techniques suitable for analysis of the GC-rich SOCS1 locus, we detected SOCS1 mutations in more than 80% of pediatric Hodgkin lymphomas (HL) and about 40% of diffuse large B cell lymphomas (DLBCL). Furthermore, a recent study demonstrated that SOCS1 inactivation in ex-vivo cultured germinal center B cells causes immortalization of these cells. It is therefore likely that SOCS1 inactivation is an important and potentially initial event in the pathogenesis of these lymphomas. We aim to perform a comprehensive investigation on the role of SOCS1 mutations in the pathogenesis of HL of young and adult patients as well as DLBCL. We plan to 1) perform a comparative study of the prevalence and pattern of SOCS1 mutations in pediatric and adult classical HL and DLBCL analyzing large numbers of samples with a sensitive sequencing technique suitable for the GC-rich SOCS1 locus, 2) identify functionally relevant SOCS1 mutations among all observed SOCS1 variants using a recently developed algorithm, 3) analyze the effects of SOCS1 inactivation in primary cultured germinal center B cells regarding proliferation, apoptosis, genomic stability, acquisition of further mutations, changes in transcriptome and activation of signaling pathways, 4) investigate the effects of functionally relevant SOCS1 mutations in competitive ORF screens in cell lines of different lymphomas and cultured primary human germinal center B cells with different SOCS1 genotypes, 5) co-express SOCS1 isoforms and potentially oncogenic variants of other genes in cell lines and human germinal center B cells to identify synergistic effects, 6) perform genome wide CRISPR/Cas9 screen in DLBCL cell lines to identify synergistic effects. The application of these complementary approaches of structural and functional genomics will reveal important novel aspects of the pathogenesis of germinal center B cell derived lymphomas.