Development and Evaluation of a Hist1/Card11-compound mutated mouse model for new treatment strategies in C4 Diffuse large B-cell lymphoma.

With a proportion of up to 35%, diffuse large B-cell Lymphoma (DLBCL) is one of the most common mature B-cell neoplasms globally. Recent efforts were able to define distinct subtypes of DLBCL differing in molecular pathways, treatment response, and clinical outcome. Multiple mutations in linker histones and aberrations in signaling molecules like NFKB and JAK/STAT define so called ‘C4 DLBCL’. Gene expression analysis revealed a subset of zinc-finger-proteins (ZNFs) significantly differentially regulated in C4 DLBCLs which interact with epigenetic modifiers like DNA-methyl transferases (DNMT1, DNMT3A/B) and Enhancer of zeste homolog 2 (EZH2) through binding of tripartite motif-containing 28 (TRIM28). Therefore, we want to develop a new mouse model mirroring genetic hallmarks of C4 DLBCL for elucidating epigenetic dysregulation in this lymphoma subtype. Furthermore, we will evaluate vulnerabilities C4 DLBCL cell lines and patient-derived xenografts to targeted therapies and multiple drug compounds.