The bcl-2 gene was the first to be identified by us through analysis of chromosomal abnormalities associated with human malignancies. Follicular lymphoma is one of the most common hematopoietic tumors in the United States and has been shown to carry a specific chromosome translocation t(14;18) which juxtaposes the bcl-2 gene and the immunoglobulin heavy chain gene, resulting in deregulation of the bcl-2 gene expression. Recent investigations, including ours, indicate that the bcl-2 gene product is involved in control of growth and/or survival of B cells. The (14;18) chromosome translocation has also been shown to be associated with some cases of diffuse B cell lymphoma which do not show a history of previous follicular lymphoma. During screening B cell tumors with bcl-2 gene probe, we have found a case of chronic lymphocytic leukemia (CLL) which juxtaposed the bcl-2 gene and the immunoglobulin lambda light chain (Ig/lambda) gene in head to head configuration. We propose to elucidate the significance of bcl-2 gene involvement in CLL development. Our preliminary data indicate that rearrangement of bcl-2 gene occurs in a significant fraction of CLL. This provides us with an opportunity that we could explore the molecular basis of the pathogenesis of CLL which is not defined yet. The bcl-2 gene rearrangement in CLL seems to be restricted to the 5' region of the bcl-2 gene which is in sharp contrast to the rearrangement in follicular lymphoma where the involvement is almost exclusively the 3' region of the bcl-2 gene. Our preliminary data also indicate that two cases of CLL carry the rearrangement of the 5' region of bcl-2 gene juxtaposed to the immunoglobulin lambda light chain gene, which also contrasts to the t(14;18) translocation which involves primarily the IgH gene. We will determine what fraction of CLL involves the bcl-2 gene rearrangement, and characterize the structure of the bcl-2 rearrangements in CLL by cloning and sequencing the breakpoints. Since no case of CLL has been described to have chromosomal abnormality at the bcl-2 locus, we will also carry out karyotype analysis of leukemic cells from patients with the bcl-2 rearrangement. We will also determine whether the bcl-2 gene expression is elevated in CLL with the bcl-2 rearrangement and identify by DNA transfection experiments DNA region responsible for the bcl-2 gene activation. These studies can help to define the molecular basis of the pathogenesis of CLL.
