This project deals with the activation of oncogenes by chromosomal translocations. We have predicted that the mouse plasmacytoma (MPC) and the human Burkitt lymphoma (BL) associated chromosome translocations act by bringing an oncogene under the direct control of an immunoglobulin gene locus. This prediction has been verified by molecular studies at other laboratories. Due to the translocation, the c-myc is juxtaposed to Ig-sequences and becomes constitutively activated. Our continued work is focused on cytogenetic and molecular problems that arise from these findings, particularly the phenotypic changes that result from the translocations and their role in the tumorigenic process. I. Cytogenetic studies will focus on the mouse plasmacytoma (MPC)-associated translocations, inversions and deletions that involve the c-myc region on chr. 15. We shall also explore the spontaneous rat immunocytomas (RIC) where we have found a (6;7) translocation that leads to the rearrangement of the myc gene. In mouse T-cell leukemia we shall analyze the role of 15-trisomy and its relationship to c-myc and a number of chr. 15 localized viral insertion sites. II. Molecular studies that relate to the cytogenetic work will focus on the analysis of the myc rearrangement and activation in the """"""""deletion"""""""" plasmacytomas. We shall attempt to clone a possible second oncogene activated by a (12;14) translocation found in two MPCs. We have cloned a rearranged c-myc gene from a rat immunocytoma and are presently characterizing the sequence transposed to it from chr. 6. On the murine T-cell lymphoma system, we are studying the possible relationships between retroviral insertion sites on chrs. 15 and 17 and the leukemia associated trisomy of these chromosomes. Somatic hybrid analysis is used in both the MPC and the T cell lymphoma system, to find possible relationships between the expression of the illegitimately activated myc-gene and tumorigenic behavior, following fusion with normal fibroblasts. III. Our studies on the regulation of c-myc expression in transfected normal and semimalignant B-cells will explore the relationship between the phenotypic effects of constitutively activated c-myc and the quantity of the protein. We shall also perform complementation experiments to explore whether the myc protein can replace certain adeno- and EB-viral functions, respectively.
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