Diffuse large B cell lymphoma (DLBCL) is a clinically and genetically very heterogeneous disease. Several [GK1] [RW2] recent studies attempted to give structure to the genetic heterogeneity by clustering cases based on their mutational profiles. Clusters MCD by Schmitz et al. and C5 by Chapuy et al. are amongst the clusters enriched for cases with particularly inferior prognosis. Both clusters are defined by mutations in MYD88 and CD79B as well as high levels of BCL2 expression and recurring mutations in transcriptional regulators of the plasmacytic differentiation process (PRDM1, SPIB). We have generated genetically-engineered mouse models that mimic key alterations of MCD/C5 DLBCL: Hallmark mutations in MYD88 and CD79B, loss of PRDM1 and overexpression of BCL2/SPIB. We could show that those mice develop clonal lesions, which morphologically resemble DLBCL. In the presence of a lesion that prevents plasmacytic differentiation (overexpression of Spib, loss of Prdm1), the forming lesions display signs of an earlier stage of B cell development, specifically histologic and transcriptomic similarities to germinal center cells. In contrast, allelic combinations without differentiation block lead to lymphomas that express CD138 and lack B220 expression, suggesting a more plasmacytic/plasmablastic differentiation status. The presence or absence of a Cd79b p.Y195H mutation has no notable effect on the immunophenotype of the lymphoma. However, its presence correlates with enrichment of BCR signaling gene set expression in lymphoma tissue and significantly increased sensitivity to inhibition of Bruton’s Tyrosine Kinase (BTK) by ibrutinib in our model systems. Taken together, we have established a set of murine models which mimic different genetic features of C5/MCD DLBCL. We have extensively characterized these models and show their usability as preclinical tools for therapeutic studies.

Citation Format: Ruth Fluemann, Julia Hansen, Benedikt Pelzer, Tim Lohmann, Ilmars Kisis, Reinhard Büttner, Thorsten Persighel, Nima Abedpour, Martin Peifer, Ron Daniel Jachimowicz, Hans Christian Reinhardt, Gero Knittel. Novel autochthonous mouse models as preclinical tools in the study of MCD/C5 DLBCL [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A21.