MOLECULAR GENETICS OF HUMAN LEUKEMIAS AND LYMPHOMAS

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It is clear that many B lymphocytic cancers are associated with characteristic chromosomal abnormalities. These chromosomal aberrations appear to result in disordered gene expression which may be fundamental to oncogenesis. The genes that are deregulated by chromosomal abnormalities and cause the malignant phenotype are called proto-oncogenes. This proposal will investigate the genetic alteration resulting from the translocation (14,18) that occurs in the majority of nodular lymphoma and the translocation(1,19) that occurs in approximately 30% of pre-B cell acute lymphocytic leukemia. We propose that two new oncogenes, bcl-2 and bcl-3, are located adjacent to these points of translocation. This proposal will focus on the cloning and characterization of these oncogenes. This project will begin with the cloning of the breakpoints noted above from genomic libraries and the identification of an adjacent transcribed gene by Northern blotting. These transcribed genes will then be cloned from cDNA libraries. The genomic and cDNA clones of these genes (bcl-2 and bcl-3) will then be characterized by restriction mapping, S1 mapping and sequencing. In an effort to understand the range of genetic alteration in these diseases, multiple tissue samples will be studied by Southern blotting, Northern blotting and perhaps at the sequence level. The cloned genes will be expressed in E. coli to isolate material to immunize for antibody production. Similarly, the derived amino acid sequence of the gene products will be used to make peptides to immunize animals for antibody production for initial protein studies. This investigation will result in an understanding of the genetic basis of human nodular lymphoma and pre-B cell acute lymphocytic leukemia. This investigation will lay the foundation for improved therapeutic and preventive strategies for these diseases.