Genesis of B lymphomas studied by functional genomics

Background: Idiotypes (Id) are antigenic determinants in the variable regions of immunoglobulins (Ig). We have previously demonstrated that B lymphocytes partially degrade their endogenous Ig and present Id-peptides on their Major Histocompatibility Compl ex (MHC) class II molecules to CD4+ T cells. In most cases this is of no consequence because T cells are tolerant. However, T cells can respond to rare Id-peptides displayed by infrequent B cells and induce B cell proliferation and differentiation. Such i nfrequent Id-driven T-B interactions usually die out within weeks without leaving traces of disease. However, we recently found in a transgenic mouse model that chronic Id-driven T-B collaboration results in development of B cell lymphomas . We have thus discovered a novel mechanism for development of B lymphomas. Moreover, since such lymphomas can be easily generated by chronic T-B interaction, they represent a rich source for study of genetic events involved in lymphoma development. Projects of the prop osal (collaborations, relation to FUGE platforms): 1) A new Ig VH knock-in mouse and a new conditional VL knock out mouse for studies on lymphoma development (The Norwegian Transgenic Center; collaboration with Klaus Rajewsky, Harvard). 2) In vivo imagi ng of lymphoma development (The Norwegian Molecular Imaging Centre; collaboration with Rune Blomhoff, University of Oslo) 3) Laser micro dissection (P.A.L.M.) of lymphoma tissue (The Norwegian Molecular Imaging Centre) 4) Analysis of lymphoma tissue by ge ne expression profiling (The Norwegian Centre for Microarray Technology) 5) Genetic events involved in lymphomagenesis analyzed by spectral karyotyping (SKY) (collaboration with Fred Alt, Harvard) and comparative genomic hybridization (CGH) (collaboratio n with Ola Myklebost, Radiumhospitalet Comprehensive Cancer Center) 6) Changes in expression of apoptosis related genes during lymphoma development (collaboration with Andreas Strasser, Melbourne).