SFB 1243:  Genetic and Epigenetic Evolution of Hematopoietic Neoplasms

• Subject Area: Biology ; Mathematics ; Medicine
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278529602

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.

• DFG Programme: Collaborative Research Centres

Completed projects

• A01 - DNA modifications in the evolution of hematopoietic neoplasms (Project Head Leonhardt, Heinrich )
• A03 - Evolution of the regulatory landscape in hematopoietic malignancies (Project Head Schotta, Gunnar )
• A04 - Dissecting aberrant functions of the ubiquitin proteasome system in the treatment-induced evolution of Mantle Cell Lymphoma (Project Head Bassermann, Florian )
• A05 - Evolution of patient derived xenograft acute myeloid leukaemia subclones in a preclinical mouse model (Project Head Jeremias, Ph.D., Irmela )
• A06 - Clinical and functional relevance of subclonal driver mutations in acute myeloid leukemia (Project Head Metzeler, Klaus )
• A07 - Clonal evolution of high risk acute myeloid leukemia (Project Head Spiekermann, Karsten )
• A08 - Evolution of transcription factor mutations in myeloid leukemias (Project Heads Greif, Philipp ;  Hiddemann, Wolfgang )
• A09 - Dissecting the clonal hierarchy in MDS and involvement of the niche in the transition to secondary AML (Project Heads Götze, Katharina Simone ;  Oostendorp, Robert A.J. )
• A10 - Identifying and targeting escape mechanisms in AML using multispecific antibody derivatives (Project Heads Hopfner, Karl-Peter ;  Subklewe, Marion )
• A11 - Contribution of somatic mutations in hematopoietic stem / progenitor cells to oncogenic evolution in follicular lymphoma (Project Head Weigert, Oliver )
• A12 - Modeling molecular and cellular mechanisms of clonal evolution in indolent B cell lymphoma (Project Head Schmidt-Supprian, Marc )
• A13 - Genetic evolution of pre-germinal center B cell lymphomas in transgenic mice with the focus on Mantle Cell Lymphoma (Project Heads Rad, Roland ;  Zimber-Strobl, Ursula )
• A14 - Assessing genetic and epigenetic heterogeneity in hematopoietic neoplasms using single cell genomics (Project Head Enard, Wolfgang )
• A15 - Tracing clonal evolution via transcriptome changes and somatic mutations (Project Head Hellmann, Ines )
• A16 - Population genetics of hematopoietic neoplasms (Project Head Metzler, Dirk )
• A17 - Computational models of neoplasmic heterogeneities and lineage choice (Project Heads Fuchs, Christiane ;  Theis, Fabian )
• MGKZ03 - Integrated Research Training Group (IRTG): Cancer Evolution (Project Heads Enard, Wolfgang ;  Subklewe, Marion )
• Z01 - Central tasks (Project Head Leonhardt, Heinrich )
• Z02 - Functional genome analysis of genetic and epigenetic evolution of hematopoetic neoplasms by next generation sequencing (Project Head Blum, Helmut )

• Applicant Institution: Ludwig-Maximilians-Universität München
• Participating University: Technische Universität München (TUM)
• Participating Institution: Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt
• Spokesperson: Professor Dr. Heinrich Leonhardt