Immune Regulation and Cancer
Head of the Group
Prof. Dr. Klaus Rajewsky
Using conditional targeted mutagenesis in mice as a main tool, we explore mechanisms of normal and malignant development in the immune system. Main topics over the last years have been the identification of signals mediating B cell differentiation and survival, the modeling of human B cell lymphomas in mice and the analysis of microRNA control in the hematopoietic system.
To model lymphomagenesis we use conditional loss-of-function and signal-on mutations of tumor suppressor genes and oncogenes known or suspected to play a pathogenic role in the human. These experiments aim at i) obtaining direct evidence for cooperating oncogenic events in lymphomagenesis in vivo, ii) identifying secondary mutations in the mouse tumors, which are also recurrent in the human and iii) studying the role of the immune system in the control of the tumors. Recent experiments along these lines have established a mouse model of sporadic Burkitt lymphoma through germinal center B cell-specific deregulation of c-Myc expression and PI3K activity, in which all characterizing features of this class of lymphoma are reproduced. Other developments have been the modeling of plasma cell tumors through c-Myc and canonical NF-kB induction, and of human Epstein-Barr-Virus (EBV) induced Post-Transplant-Lymphoproliferative Disorder (PTLD) through B cell-specific expression of the EBV protein LMP1. This latter mouse model reproduces not only EBV-driven lymphomagenesis, but also the immune surveillance of these tumors, leading to a novel therapeutic approach based on the recognition of the tumor cells by natural killer cells. Our EBV related experiments are embedded in a broader project of modeling Hodgkin lymphoma, in collaboration with Martin Janz and Stefan Mathas from the Doerken group.
Until the end of 2011 the work was mainly carried out at the Program in Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, USA. Since the beginning of 2012 the group is fully located at the MDC.