Klaus Rajewsky


Division of Pathology, Department of Medicine
Harvard Medical School
Warren Alpert Building, Room 153-154
200 Longwood Avenue
Boston MA 02115
Tel: (617) 278-3067
Fax: (617) 278-3129
Email: rajewsky@cbr.med.harvard.edu
14 postdoctoral fellows, 1 graduate student


The work of the group focuses on the control of normal and malignant development of cells of the immune system, with a special emphasis on antibody-producing cells, B lymphocytes. A major experimental approach, which we use in our work, are gene targeting techniques applied to mouse embryonic stem cells, which allow one to genetically analyze gene function in vivo. Specifically, we have developed and refined over the years conditional gene targeting, by which specific mutations can be introduced into the mouse in a cell type-specific and/or inducible fashion. This includes the conditional inactivation or activation of genes of interest, as well as the construction of genetic switches through which cells can switch from the expression of a given gene to that of another.

 

Using this approach, we investigate molecular mechanisms, which control early B cell development, the homeostasis of mature B cells, the generation of memory B cells and plasma cells upon the activation of mature B cells by antigen and their recruitment into the germinal center response, and the generation of B cell lymphomas. B cell lymphomas, a major and increasingly severe problem in the clinic, arise mostly as a result of the germinal center reaction. In this reaction, massive proliferation of the cells in concert with programmed mutational events (somatic hypermutation and class switch recombination) allows, in normal physiology, the generation of memory B cells and plasma cells producing antibodies binding antigen with high affinity, but at the same time produces a “physiological” risk of malignant transformation of the participating cells through mutations that go wrong. A major aim of our work is to generate mouse models of human B cell lymphomas, by the targeted activation of oncogenes and signaling cascades in germinal center B cells, through the methods of conditional gene targeting which we have developed.

 

A recent major effort of the group addresses the role of RNA interference (RNAi), especially of microRNAs, in immune development and control. By inactivating basic components of the RNAi machinery in the mouse germ line or conditionally in lymphocytes, we have found that lymphocyte differentiation heavily depends on this machinery. Current work assigns specific regulatory functions in the control of lymphocyte differentiation to individual microRNAs, identifies the target genes that are critically involved in this control and attempts to elucidate mechanisms by which deregulated microRNA expression contributes to lymphomagenesis.

 

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BBS webpage updated 12/02/2009