Regulation of Proliferation and Differentiation of B cells and the Development of Lymphomas

Antibody diversity is achieved by random recombination of immunoglobulin (Ig) gene segments in developing B lymphocyte precursors. While this process is essential to yield highly diverse antigen receptors, defects in lymphocyte development or activation may result in immunodeficiency, autoimmunity or leukaemia. The aim of our research is the characterization of molecular processes that regulate the normal development of B cells and the mechanisms that underlie malignant B lymphocyte transformation.

The B cell antigen receptor (BCR) is a central regulator of B lymphocyte differentiation and proliferation. In this project, we are interested in how signalling from BCRs may promote lymphoma development and whether there are structural and/or functional features specific for BCRs expressed on lymphoma cells. Based on our previous studies on autonomous signalling of BCRs from polyreactive B cells, we have characterized BCRs from patients with Chronic Lymphocytic Leukemia (CLL). We could show that, in contrast to other B cell neoplasias, such as Multiple Myeloma, Mantle Cell Myeloma, Marginal Zone Myeloma and Folicular Lymphoma, CLL-derived BCRs induce antigen-independent, cell-autonomous signalling which is dependent on a region of the heavy chain (HC) called heavy chain complementarity determining region 3 (HCDR3) and an internal epitope in framework region 2 of the BCR-HC (Figure 1). Transferring the HCDR3 of CLL-derived BCRs confers autonomous signalling capacity to non-autonomously active BCRs, whereas mutations in the internal epitope abolish this capacity. In this ongoing project, we further characterize structural and functional features of BCRs from lymphoma patients and are in the process of identifying bio-molecules suitable to specifically influence signalling from autonomously active receptors.