ORGANIZATION AND CONTROL OF GENETIC MATERIAL IN PLASMACYTOMAS

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The overall goal of this research is to study the activation of particular genes in diseased and normal cells in order to understand which genes may play important roles in the development of malignancies, autoimmune diseases and normal differentiation. The immune system has been chosen as the central focus of this research, and we have concentrated on the expression of "oncogenes," especially myc, myb, ras and bc1-2, as well as immunoglobulin and T cell receptor genes. To this end we have been studying the lymphoid tumors (particularly the plasmacytomas) that are regularly induced in BALB/cAnN mice by intraperitoneal injections of alkane mineral oils, such as pristane. These tumors represent immortalized lines of B lymphocytes or myeloid cells at different stages of differentiation. Currently we are using this model system of tumors to learn how the genes involved in myeloid and B cell carcinogenesis are organized and regulated. The activation of the myc oncogene has been clearly shown to be essential to the induction of plasma cell tumors, but it is likely that other genes must also be activated to complete the neoplastic transformation. The ras family of oncogenes is a likely candidate and we have evidence that mutations in one or more of these genes can be found in plasmacytomas and lymphosarcomas. The role these play in generation of these tumors is being studied. The myb gene is expressed in most hematopoietic tumors, and in certain virus= induced myeloid malignancies it is activated by insertion of a virus within the coding region. The regulation of this gene's expression is being investigated, and one example of alternative splicing of an extra coding exon has been found in normal and malignant cells. The putative proto-oncogene, bc1-2, appears to be expressed in a differentiation stage-specific and cell type- specific manner. Whether excess bc1-2 expression is tumorigenic in mice is being tested using retro- viral constructs.