ORGANIZATION AND CONTROL OF GENETIC MATERIAL IN PLASMACYTOMAS

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Our research goal is to identify and understand the genes whose altered structure or expression play critical roles in malignancy, immune diseases and normal differentiation. We are concentrating on the expression of a group of these "oncogenes": abl, bcl-2, myb, and myc, as well as the potential oncogenes, Pvt-1 and Protein Kinase C (PKC), in mouse hemopoietic tumors. Deregulated expression of 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, and we have shown that this locus is transcribed at very low levels in normal cells but in much higher amounts in some plasmacytomas. Normally Pvt-1 transcripts are ca. 14 kb in length, suggesting that the Pvt-1 locus is very large. In some plasmacytomas with chromosomal translocations in the Pvt-1 locus. the Pvt-1 transcripts are truncated and form chimeras with Ig kappa chain transcripts. We have isolated a cDNA for mouse bcl-3 (on human chromosome 19) and have mapped it to mouse chromosome 7. During B-cell differentiation its expression is maximal in cells that have not undergone Ig isotype switch. This suggests that the chromosome translocations involving this locus that characterize some CLL's occur in this stage. The ABL-MYC retrovirus, expressing v-abl and c-myc, rapidly induces intra-peritoneal plasmacytomas in BALB/c and other strains of mice, even in the absence of i.p. oil and in the absence of helper virus. If the mice are preimmunized with lysozyme or sheep red blood cells, about 60% develop tumors producing antibody specifically directed against the immunogen. This may prove to be a useful alternative to hybridoma technology for generating monoclonal antibodies.