DNA sequences near the site of reciprocal recombination between a c-myc oncogene and an immunoglobulin switch region.

Abstract

The chromosomal translocations found in many B-cell tumors result in the joining of a c-myc oncogene with an immunoglobulin heavy chain switch region. This finding is striking because the natural function of switch regions is to mediate DNA rearrangements important to the maturation of immune responses. These normal switch rearrangements are probably mediated by specific enzymes. In this paper we report the isolation of the two reciprocal products of a recombination between a cmyc gene on murine chromosome 15 and an immunoglobulin switch region (SAS72b) on chromosome 12. We have determined the sequences of these DNA molecules near the recombination sites and show that the recombination is nearly perfectly reciprocal, with a seven-nucleotide deletion. An examination of the sequences reported in this paper, and of sequences published by other authors, shows a correlation between the points of recombination for c-ayc-S segment rearrangements and for normal heavy chain switches. We suggest that this correlation implies a role for switch recombination enzymes in creating substrates for the c-myc recombination. The c-myc gene also seems to share some limited homology to sequences thought to be important in heavy chain switching. Finally, we discuss a working model that accounts for some characteristics of c-myc-S segment recombinations. The model also suggests-a mechanism for increased transcriptional activity of the rearranged c-myc oncogene in B-cell tumors.

Interruption of two immunoglobulin heavy-chain switch regions in murine plasmacytoma P3.26Bu4 by insertion of retroviruslike element ETn.

“…This arrangement is consistent with the restriction map of -yM8.5, the site of insertion described above, and the fact that most ETn elements are 6.0 kb in length. The sequences at the Six/S-yl recombination site of -yM8.5 (not shown) were identical to those in the IF2 expressed gene (13) and to those in pB.12, a BamHI clone we describe elsewhere (Petrini et al, J. Immunol., in press) that overlaps the 11.1-kb EcoRI fragment.…”

“…As shown in Fig. 6 This fragment represents one of the two IgH alleles in the progenitor of P3, the other being the c-myc translocation described elsewhere (13,30). This insertions begins exactly at the 5' boundary of previously described ETn LTR sequences; the insertions may represent transpositions of the element.…”

Regulation of the human c-myc gene: 5' noncoding sequences do not affect translation.

“…Recent models of c-myc regulation have suggested that the mvc protein is involved directly or indirectly in its own regulation (14,25). In a translational control model, a regulatory molecule might bind to the mRNA, presumably in exon 1, to directly inhibit translation or destabilize the mRNA so that it could not be translated.…”

Immunoglobulin synthesis and gene rearrangements in lymphoid cells transformed by replication-competent Rauscher murine leukemia virus: transformation of B cells at various stages of differentiation.

“…The two cell lines [71-2 and 85] with c-myc rearrangement possess heavy chain rearrangements without the expression of ,u chains; but the c-myc rearrangement does not seem to involve CA or Ca switch regions. In this respect the rearrangement of the c-myc differs from that of IgA-producing plasmacytomas and IgMsynthesizing Burkitt lymphomas (Shen-Ong et al, 1982;Marcu et al, 1983;Adams et al, 1983;Cory et al, 1983;Dunnick et al, 1983). The rearrangement of the c-myc observed in cell lines 85 and 71-2 may be due to the integration of R-MuLV near the myc gene.…”