Lymphomas and Leukemias

B and T lymphocytes play a crucial role during adaptive immune responses. By sequential recombination processes in the bone marrow and the thymus, lymphocytes acquire unique forms of antigen receptors, which are specific for certain antigens. These recombination processes are associated with DNA double strand breaks and bear therefore the risk to lead accidentally to the occurrence of reciprocal translocations driving lymphoma development. Two main groups of lymphomas are distinguished by the World Health Organization (WHO) classification - Hodgkin-lymphomas and Non-Hodgkin-lymphomas (NHL). Currently 28 new cases of lymphomas per 100.000 people are diagnosed each year. Among these are 95% B cell lymphomas and 5% T cell lymphomas. The higher incidence of B cell lymphomas in comparison to T cell lymphomas might be due to two additional genetic processes - somatic hypermutation and class switch recombination, which occur during the germinal center reaction. These genetic processes, which are also associated with double strand breaks take only place in B but not in T cells. In fact most of the B cell lymphomas originate from germinal center and post-germinal center B cells. Besides mutations and translocations occurring during the generation and activation of lymphocytes, viruses have been associated with the development of B and T- cell lymphomas. In particular the Epstein-Barr Virus (EBV) has a strong association with Burkitt´s Lymphomas (BL), Hodgkin-Lymphomas (HL), Posttransplant Lymphomas (PTLD) and Primary Effusion Lymphomas (PEL). It is assumed that EBV contributes to lymphoma development by expressing viral proteins that mimic constitutive active forms of cellular receptors, which are involved in B cell differentiation and activation. Especially in HL and PTLD the viral proteins LMP1 and LMP2A mimicking constitutive active forms of the CD40 and B-cell receptor (BCR) are supposed to contribute to the pathogenesis of these lymphomas. Focus of our research is to study the pathogenesis of lymphoma entities that are correlated with EBV. In particular we are interested in the contribution of the viral proteins EBNA2, LMP1 and LMP2A and their constitutive active cellular counterparts Notch, CD40, BCR to the development of B cell lymphomas. The final aim of our studies is to develop novel therapies for a better treatment of these lymphoma entities.

In addition to processes in lymph nodes, malignant transformation of lymphocytes might take place in the bone marrow during normal hematopoiesis, causing a systemic tumor called leukemia. Acute leukemia (AL) represents the single most frequent malignant disease in childhood responsible for numerous cancer-related deaths in children, but also a frequent and severe challenge in adults. Novel treatment approaches are urgently needed for patients with AL. State of the art treatment of AL involves chemotherapy followed by bone marrow transplantation.

Our aim is to translate novel therapeutic approaches from basic research to clinical studies on AL patients. Towards this aim, we perform preclinical treatment trials on patients' AL cells growing in mice which are monitored by in vivo imaging due to lentiviral cell engineering. Close collaboration with clinicians from both Munich Medical Faculties of both TUM and LMU as well as collaboration with national and international clinical multicenter studies enables a direct translation of novel therapeutic options into clinical trials for patients suffering AL.

AG B-cell development and activation