Human hematopoietic neoplasms, leukemias and lymphomas are very often associated with chromosomal abnormalities such as chromosomal translocations and inversions, which are believed to play crucial roles in pathogenesis of malignant diseases because chromosome abnormalities can activate c-oncogenes by juxtaposing them to actively transcribed loci. About 90% of follicular lymphoma of B-cell origin, one of the most common hematopoietic malignancies, carry a specific chromosomal translocation between chromosome 14 and 18, t(14;18). By cloning the joining region of the translocation, we have identified a gene that has been named bcl-2. All t(14;18) translocations studied thus far occur within or in close proximity to the bcl-2 gene, and the level of bcl-2 MRNA and transcription of tranlocated bcl-2 allele are elevated in the lymphoma cells with the t(14;18) translocation. These make the bcl-2 gene a strong candidate for the gene which plays the dominant role in follicular lymphomagenesis. We propose to analyze the function of the bcl-2 protein. We constructed the high expression forms of the bcl-2 gene and introduced into B cell lines. Our preliminary results indicate that a high level of bcl-2 protein reduced serum requirement for growth of B cell line. The effect on cell growth by bcl-2 protein will be studied in more detail by assaying the growth potential in soft agar and in serumdeprived nedium, and the plating, efficiency after serial dilution and tumorigencity in athymic mice. We will then determine which lymphokine(s) is involved in growth advantages given to 8 cells by high levels of bcl-2 protein. The cell lineagespecificity of the growth effect produced by bcl.2 protein also will be analyzed. A series of mutant bcl-2 genes will be generated and used to determine the region of the bcl-2 protein that are important for the growth-enhancing activity of the protein. These studies can help to define the molecular basis of B cell malignancy.
