ORGANIZATION AND CONTROL OF GENETIC MATERIAL IN PLASMACYTOMAS

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Our research goal is to understand the genes whose altered structure or expression play critical roles in malignancy, autoimmune diseases and normal differentiation. We are concentrating on the expression of a group of these "oncogenes": abl, bcl-2, bcl-3 and myc, as well as the potential oncogenes, Pvt-1, Protein Kinases C (PKC) and cyclins, in mouse hemopoietic tumors. Deregulated expression on myc secondary to chromosome translocation has been shown to be one essential component of the genetic alterations involved in oil-induced i.p. plasmacytomas in BALB/c mice. Some of these myc-activating translocations occur 200-300 kb 3' of c-myc in a region called Pvt-1. We have shown that this locus is transcribed at very low levels in normal cells but in much higher amounts in some plasmacytomas and in certain B lymphocytic cell lines in which both c-myc and Pvt-1 genes are amplified. Normal splenic lymphocytes and NIH3T3 cells increase their expression of Pvt-1 following mitogenic stimulation, suggesting that Pvt-1 is a new member of the "early response" genes, although its function remains unknown. Human and mouse homologies have been detected, indicating evolutionary conservation and implying a function that is essential to normal growth or development. The ABL-MYC retrovirus, expressing v-abl and c-myc, rapidly induces intraperitoneal plasmacytomas in BALB/c and other strains of mice that are resistant to pristane-induced plasmacytomagenesis. If the mice are preimmunized, 50% develop tumors producing antibody specifically directed against the immunogen. This has already proved to be a useful alternative to hybridoma technology for generating monoclonal antibodies to a variety of antigens. Seven isozymes of the PKC family have been shown to be expressed in a cell- type specific fashion in hemopoietic cells and cell lines. These serine- threonine kinases have been shown to change the phenotype of NIH3T3 cells when overexpressed by transfected expression vectors, and immunofluorescent studies with isotype-specific antibodies indicate that each isotype translocate to different subcellular locations after its kinase activity has been activated by phorbol ester. Similarly, overexpression of certain PKCs in mouse myeloid cell lines imparts to these cells the ability to respond to phorbol ester stimulation by differentiating into macrophages.