We are studying the DNA rearrangements that form immunoglobulin genes and those that have activated oncogenes in lymphoid tumors. We will analyze assembly of the heavy (H) chain V-region gene from its V?H?, D?H?, and J?H? gene elements by examining partially assembled (D?H?-J?H?) structures in T lymphomas, including several lines with functional D?H?-J?H? recombination machinery, and aberrantly recombined J?H? alleles in a plasmacytoma. Analysis of pre-B lymphoma lines blocked in H-chain expression should provide insights into an activation step subsequent to V?H?-D?H?-J?H? assembly. The discovery that the predominant chromosome translocations in murine plasmacytomas and human Burkitt lymphomas activate the cellular myc oncogene by fusion to the immunoglobulin H-chain locus, calls for detailed analysis. We have sequenced the mouse and human c-myc genes, mapped 31 tumor breakpoints, and described altered c-myc transcripts in 30 tumors reflecting new promoters. We have studied the translocation mechanism by sequencing the fusion regions in five tumors and wish to identify the new c-myc promoters and to determine whether they are activated by a C?H?-locus enhancer. We are also studying variant translocations, which involve light-chain loci, to determine whether they activate c-myc or another oncogene. To analyze oncogene activation in T lymphomas, we are studying several lines with retroviral inserts near c-myc. We are also testing several other potential oncogenic sequences from murine chromosome 15, which is implicated in T-lymphoma induction. Since lymphoma induction by Abelson Murine Leukemia Virus (A-MuLV) may require not only the retroviral abl gene but also activation of a cellular oncogene, we will test the possibility that integration of A-MuLV near specific genes promotes tumorigenicity. Since cooperation of a myc-like """"""""immortalizing"""""""" oncogene and a ras-like oncogene permits induction of foci in primary fibroblasts, we will use this complementation test to define the oncogenic regions of myc and attempt to establish an assay for new immortalizing genes in tumor DNAs. (AB)
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