Research proposed in this application will investigate a number of genetic problems directly or indirectly related to human B cell neoplasia and having both clinical and basic biologic ramifications. Five projects are planned. These involve the following: (1) Analysis of the multi-clonality of lymphoproliferative lesions in immunosuppressed patients. This project will utilize restriction fragment length polymorphisms of the fused termini of Epstein-Barr virus genomes as markers of clonal cellular proliferation to determine whether or not separate lymphoproliferative lesions in individual patients arise from independent transformation events. (2) Analysis of human non- immunoglobulin gene DNA which contains strong sequence homology to DNA of the immunoglobulin heavy chain enhancer region. In addition to cloning, sequencing, and mapping this DNA on the human genome, studies will be carried out to determine possible functions of this DNA and its flanking sequences. (3) Molecular cloning and structural analysis of DNA corresponding to cytologic breakpoints involved in the t(4;11)(q21;q23) chromosomal translocation of common acute lymphocytic leukemia. DNA sequences cloned in this project will be used as hybridization probes to analyze sites of rearrangement and transcription in human B cell tumors. (4) Investigation of somatic hypermutation in rearranged immunoglobulin genes of B cell lymphomas and cell lines. The basic biology of somatic mutation will be studied by cloning and sequencing immunoglobulin genes and cDNA from tumors and cultured cells. Attempts will also be made to develop an in vitro tissue culture system for analysis of somatic mutation in both endogenous and transfected immunoglobulin genes. (5) Investigation of the possible evolution of multiple myeloma from myeloma-related clonal B cells. Immunoglobulin DNA cloned from bone marrow and blood specimens of myeloma patients will be analyzed to determine whether or not the neoplastic plasma cells in this disease develop by a multistep mechanism involving clonal B cells. In addition, this project will investigate somatic mutation in the immunoglobulin genes of plasma cells and their late B cell precursors.
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