Plasmacytoid tumours in mice and Burkitt's lymphomas in humans display characteristic chromosomal translocations involving the c-myc proto-oncogene. Models to explain quantitative changes in c-myc expression have been proposed based on the loss of normal promoters as a result of translocation. However, alternative explanations, such as somatic mutation are needed to explain altered c-myc expression in the absence of gene breakage. We present here the nucleotide sequence of the normal murine c-myc gene. Comparison of this sequence with that of a translocated c-myc gene from a murine plasmacytoma reveals complete identity of coding sequence. One nucleotide difference was found in the non-coding first exon. This shows that qualitative changes of the c-myc gene product are not required for oncogenesis in murine plasmacytomas. In contrast, mutations are found in coding and non-coding regions of translocated c-myc genes from Burkitt's lymphomas, suggesting that the mechanisms by which c-myc is activated in plasmacytomas and Burkitt's lymphomas are different.

Chromosomal rearrangements involving the c-myc oncogene are a prevalent feature of plasmacytomas that arise after inoculating BALB/c mice with pristane and Abelson murine leukaemia virus (A-MuLV). With this observation in mind, we decided to determine if any genetic alterations of the c-myc locus could be observed in cells of a different type, when transformed in vitro by A-MuLV. Here we have analysed three independent A-MuLV-transformed NIH 3T3 lines (ANN-I, 54c12 and N25), and found that the c-myc locus is amplified 8-19-fold in each transformant. Quantitative S1 nuclease mapping performed on ANN-I and 54c12 RNAs demonstrated that: (1) c-myc messenger RNAs accumulated to double the levels found in NIH 3T3 cells; and (2) a shift in the use of the two normal c-myc transcription initiation sites (P1 and P2) occurred in favour of the 3' site, P2. Analysis of c-myc chromatin by DNase I treatment of 54c12 nuclei revealed that most, if not all, of the c-myc gene copies were transcriptionally competent. We present alternative ideas to explain why amplification of the c-myc gene occurs repeatedly in A-MuLV-transformed fibroblasts. Finally, we discuss our results in relation to the hypothesis linking the phenomenon of tumour progression with the amplification of oncogenes.

Presented is a detailed molecular analysis of the rearranged c-myc oncogene from ABPC45, an unusual plasmacytoma that was originally classified as translocation-negative. Previous data obtained by high-resolution chromosome banding suggested that this tumor was a member of a small group distinguished by the absence of rcpt (12;15) or (6;15) and further characterized by a band deletion near the c-myc locus on chromosome 15. However, genomic Southern blotting and analysis of the cloned oncogene in the present study reveal that (i) chromosome 12 sequences lie 365 base pairs 5' of the rearranged c-myc; (ii) this DNA consists of immunoglobulin alpha switch region and 5' immunoglobulin mu switch region sequences that are rearranged in an aberrant fashion; and (iii) the immunoglobulin heavy-chain gene enhancer element now resides approximately 2.5 kilobase pairs 5' of c-myc. We infer from these and other data that the rearrangement of c-myc in ABPC45 occurred via a multistep switch region-mediated process and that a reciprocal translocation has indeed taken place. Unlike many other plasmacytomas, this event did not interrupt the normal c-myc transcription unit. Rather, disruption of gene regulation is manifested in part by a change in relative usage of the two promoters normally used by the unrearranged gene. In contrast to several of its counterparts in Burkitt lymphomas, DNA sequence analysis of the translocated c-myc gene of ABPC45 reveals that it has not acquired point mutations in the noncoding first exon. These results strongly imply that a cis-acting regulatory element normally located 5' of exon 1 is lost and that heavy-chain constant region or enhancer sequences exert similar cis effects on translocated c-myc loci.