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Modeling lymphoma pathogenesis in mice - from basic mechanisms to pre-clinical models

Final Report Summary - LYMPHOMA (Modeling lymphoma pathogenesis in mice - from basic mechanisms to pre-clinical models)

B cell lymphomas are the most frequent cancers in the hematopoietic system. This is because they derive from antibody forming cells, called B cells, which undergo reshuffling and mutation of the genes encoding antibodies during their differentiation; and that mutation predominantly happens when the cells massively proliferate in immune responses in structures called germinal centers (GCs), in order to produce high-affinity antibodies: Concomitant mutation (accompanied by breaks in the genetic material, the DNA) and cell proliferation promote oncogenic mutations and thus make the cells prone to become malignant.

The analysis of human B cell lymphomas has indeed shown that although they fall into several classes, most of them derive from GC or post-GC, i.e. mutated, B cells. The rationale of the work pursued in the LYMPHOMA Advanced ERC Grant was to model human B cell lymphomas in mice by introducing into these animals mutations or combinations thereof that are recurrently found in those lymphomas and thought to be drivers of tumor growth. The resulting mouse models of human lymphomas would allow us to i) functionally verify presumed driver mutations, ii) search for additional accumulating recurrent mutations in the mouse tumors, assess their functional impact and search for counterparts in human tumors, and iii) finally come up with new insights into lymphoma pathogenesis and potential new therapeutic targets/approaches.

Following this general scheme, we have generated mouse models of several human B cell lymphomas, such as Burkitt Lymphoma (BL), various forms of Diffuse Large B Cell Lymphoma (DLBCL) and Epstein-Barr-Virus (EBV) driven B cell lymphomas and lymphoproliferative disorders. In all cases these mouse models have been mechanistically informative with respect to new insights into molecular signaling and transcriptional pathways driving tumorigenesis, mechanisms of immune surveillance protecting against tumor growth, and implications of our findings for tumor therapy.

An unforeseen, but high-impact component of our research has been the incorporation of CRISPR/Cas9 mediated targeted mutagenesis into our experiments and its technical improvement. The latter included an enhanced efficiency of gene replacement and repair, as well as a Cas9 transgenic mouse model allowing highly efficient genetic screens in primary hematopoietic and other cells. Overall, this approach allows precise modification of genes in cells and organisms in an unprecedented way, including the repair of unwanted mutations. We are now using CRISPR/Cas9 driven mutagenesis not only for the generation of new mouse models of diseases such as Multiple Myeloma and others (work in progress), but also for the development of somatic cell therapy of inherited EBV related fatal lymphoproliferative diseases, first in our mouse models, but ultimately in the human.