6;7 chromosomal translocation in spontaneously arising rat immunocytomas: evidence for c-myc breakpoint clustering and correlation between isotypic expression and the c-myc target.

Abstract

Our previous studies have shown that spontaneously arising immunocytomas in the LOU/Wsl strain of rats contain a t(6;7) chromosomal translocation in all seven tumors studied (F. Wiener, M. Babonits, J. Spira, G. Klein, and H. Bazin, Int. J. Cancer 29:431-437, 1982). We have also shown that the c-myc is located on chromosome 7 (J. Sumegi, J. Spira, H. Bazin, J. Szpirer, G. Levan, and G. Klein, Nature (London) 306: [497][498][499] 1983) and the immunoglobulin H cluster on chromosome 6 (W. S. Pear, G. Wahistrom, J. Szpirer, G. Levan, G. Klein, and J. Sumegi, Immunogenetics 23:393-395, 1986). We now report a detailed cytogenetic and molecular analysis of nine additional rat immunocytomas. The t(6;7) chromosomal translocation is found in all tumors. Mapping of the c-myc breakpoints showed that in 10 of 14 tumors, the c-myc breakpoints are clustered in a 1.5-kilobase region upstream of exon 1. In contrast with sporadic Burkitt's lymphoma and mouse plasmacytoma, only 1 of 14 tumors contains the c-myc breakpoints in either exon 1 or intron 1. Analysis of the sequences juxtaposed to the c-myc show that immunoglobulin H switch regions are the targets in at least five tumors and that there is a strong correlation between the secreted immunoglobulin and the c-myc target. Unlike sporadic Burkitt's lymphoma and mouse plasmacytoma, at least two rat immunocytomas show recombination of the c-myc with sequences distinct from immunoglobulin switch regions.Consistent chromosomal translocations are thought to play an important role in the development of certain neoplasms (10, 21). The role of specific translocations has been extensively studied in two B-cell tumors, Burkitt's lymphoma (BL) and mouse plasmacytoma (MPC), and chromosomal translocations have been identified in 100% of the former and 95% of the latter type of tumor (22). BL and MPC represent different stages of B-cell maturation; however, the chromosome translocation in both tumors involves the chromosomes containing one of the immunoglobulin loci and the c-myc cellular oncogene (23). The translocation is believed to act by constitutive activation of c-myc (9). Recent facsimile experiments have shown that constitutively activated c-myc genes can induce tumors in an appropriate host environment (1,24,27

The “missing” mouse plasmacytoma (MPC) associated translocation T(15;16) occurs repeatedly in new MPC induction systems

“…Similar conclusions were reached about the equally regular association between Iglmyc translocations and to other B-cell derived tumors, human Burkitt's lymphomas (BL) (Magrath, 1990), and rat immunocytomas (Pear et al, 1988).…”

Deletional remodeling of c-myc-deregulating chromosomal translocations

“…12 (Gerstein et al, 1990). Additional examples of rearrangements suggestive of having occurred in trans have been described with the integration of a long interspersed nuclear element (LINE) next to the Se region in a rat plasmacytoma (Pear et al, 1988) and the interruption of the Sg2a region in a mouse plasmacytoma by an early transposon-like element, E.Tn (Elenich and Dunnick, 1991). Examples in which switch recombinase may have been instrumental in generating inappropriate intrachromosomal rearrangements include the recombination of a LINE-1 element with the expressed Igh cluster in a subline of mouse plasmacytoma MPC 11 (Bard and Birshtein, 1995) and the ®ndings of this study.…”

Identity of rearranged LINE/c-MYC junction sequences specific for the canine transmissible venereal tumor.

“…Some of these sequences can function as mobile genetic elements and transpose from one place to another in the mammalian genome (17)(18)(19)(20). Several examples of integration of transposable elements in the vicinity of oncogenes and other cellular genes in tumors have been described (6,7,(11)(12)(13)(14)(21)(22)(23)(24)(25)(26). Such tumor-specific somatic mutations can serve for the detection of minimal residual disease by PCR.…”