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 disease 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 and ras, 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. Generally oil-induced plasmacytomas arise only after a long latent period, typically 12 months. In such a long time period many genetic changes could have accumulated, one or more of which could be causally involved in the carcinogenic process. The latent period can be drastically shortened by injecting certain retroviruses, e.g., Abelson virus complex or viruses incorporating avian v-myc genes. The latency period is shortened presumably by supplying one of the genetic lesions that by chance arose in the oil-treated peritoneal cells. We have also studied how endogeneous proto-oncogenes are expressed and found the frequent elevation of steady state levels of RNA from the proto-oncogenes c-myc and c-myb in certain tumors, autoimmune cells, and in dividing normal lymphocytes. Recent studies have shown changes in some of the ras family of oncogenes in a large number of these tumors. The details and consequences of these mutations are currently being analyzed. Another putative oncogene, bcl-2, has been found to be expressed at only certain periods during B cell differentiation. An extensive effort has been made to characterize the structure and control of expression of these oncogenes in normal and abnormal cells.