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

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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.