SFB 1243: Genetic and Epigenetic Evolution of Hematopoietic Neoplasms

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The major challenge in cancer therapy is the capacity of tumors to evolve and thereby escape selection pressures imposed by the body and by therapies. This evolutionary process is fueled by random genetic and epigenetic changes, making tumors with their billions of cells a diverse and moving target. Any therapy therefore needs to capture and tackle the molecular heterogeneity of tumor cells in different cancers and individual patients to ensure lasting success. Especially in the era of molecularly targeted cancer therapies, anticipating possible escape routes and effectively blocking them by suitable drug combinations and/or dosing regimens is critical. Informed treatment decisions are ideally based on a comprehensive understanding of how genetic and epigenetic alterations and the clonal composition of tumors determine the evolution of therapy resistance and which specific vulnerabilities can be exploited. The close integration of clinical, molecular, computational and evolutionary expertise within this CRC enables us to identify, quantify and model the molecular processes and parameters that lead to the initial emergence of hematopoietic neoplasms, their evolution towards therapy resistance and the influence of the microenvironment. Within this CRC, we coordinately study myeloid and lymphoid neoplasms focusing on myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), follicular lymphoma (FL), multiple myeloma (MM) and mantle cell lymphoma (MCL). We study clonal hematopoiesis and its underlying epigenetic mechanisms, the role of the bone marrow niche and the immune microenvironment, the rate and mechanism of (epi)genetic evolution with and without drug treatment and disease resistance mechanisms to apoptosis inducers, antibody-based immunotherapies and proteasome inhibitors. As there is no single perfect model system, we take an integrated approach combining cell culture systems, xenotransplantation models and genetically modified mice, all closely linked with the analysis of patient-derived material and data from clinical trials. We are convinced that this interdisciplinary approach will promote a better understanding of the basic processes of tumor evolution and ultimately improve therapy and patient outcomes.