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We are interested in oncogenic events and potential cellular counteractions in the process of lymphomagenesis and their subsequent implications for treatment outcome. Stresses such as oncogenic activation, but also chemotherapeutic DNA damage challenge cellular safeguard programs – namely the death program apoptosis and the arrest program cellular senescence – both enforcing an irreversible cell-cycle exit (Fig. 1A, B). Therefore, genetic defects in apoptotic or senescent pathways acquired during tumor formation may anticipate insensitivity to subsequent exposure to therapy. To genetically dissect and to therapeutically exploit key genetic lesions during B-cell lymphomagenesis and in chemoresistant scenarios is the central goal of my laboratory. Moreover, recent evidence points towards interferences between cell-autonomous failsafe programs and the tumor environment, which, in turn, evoke feedback mechanisms that may significantly alter tumor biology.
Utilizing tractable transgenic mouse models that closely recapitulate genetics, histology and clinical behavior of human aggressive lymphomas, we introduce gain- or loss-of-function genetic alterations by knock-out cross-breeding or retroviral manipulation of lymphoma progenitor or hematopoietic stem cells to generate series of individual lymphomas that harbor defined genetic defects. Subsequently, we test treatment responses of those lymphomas after their transplantation into immunocompetent recipient mice in settings that parallel clinical trials (Fig. 1C).
Our strong participation of our clinical department in lymphoma trial activities, the high number of lymphoma patients referred to our unit and the well-established collaboration with our Charité colleagues of the Lymphoma Reference Pathology Department allow us to rapidly verify novel mouse model-based findings in lymphoma specimens from actual patients.
We are participating in various research consortia, including the DFG-funded SFB/TRR54 "Growth and Survival, Plasticity and cellular Interactivity of lymphoid Malignancies" and collaborate with international partners, but also colleagues at the Max-Delbrück-Center for Molecular Medicine in Berlin-Buch, a non-university research institution of the Helmholtz Society, to explore pathogenesis and novel therapeutic aspects of aggressive lymphomas. We are investigating the biological and therapeutic implications of numerous candidate genes or pathway defects in aggressive lymphoma, and focus in particular on the effect of those defects on cellular senescence and other stress response programs. Current projects aim to integrate more complex aspects of lymphoma biology, i.e. functional alterations due to transdifferentiation processes and interactions between proliferating tumor cells, their non-proliferating senescent and pre-apoptotic neighbor cells as well as the cross-talk between those functionally different tumor cells and components of the tumor stroma and the host immune system.