To understand normal and abnormal B lymphocyte development, we have undertaken studies to identify and characterize genes important in these processes. We characterized the t(14;18)(q32;q21) chromosomal translocation present in human follicular lymphoma and identified a candidate transforming gene at 18q21. This gene, termed BCL2, is presumably also important in normal pre-B-cell development. We have analyzed both germline substrates and derivative products of the t(14;18) translocation to define the mechanism of this exchange. To elucidate the structural consequences of this recombination, we sequenced normal and translocated BCL2 cDNAs. The normal BCL2 gene uses six potential polyadenylation signals in exon 3 and two different 5' exons (exons 1 and 2) with their respective promoters. The t(14;18) translocation results in the deregulated expression of chimeric BCL2/IgH mRNA transcripts with somatic mutations in the BCL2 protein coding region. We have developed antibodies to the BCL2-predicted protein that should help define the function of the normal and translocated BCLZ protein. We have extended the approach of identifying new putative proto- oncogenes by cloning chromosomal breakpoints to the analysis of Hodgkin's disease and have cloned potential breakpoints within the immunoglobulin heavy chain (14q32) and T-cell receptor beta chain (7q35) loci. Finally, we screened an expression lambda gtll library with an antibody that recognizes a 12-kDa lymphocyte activation antigen and identified one positive clone. Further analysis of these transforming and activation genes should provide important insights into B-cell transformation/differentiation.
