Differences in the molecular structure of c-myc-activating recombinations in murine plasmacytomas and precursor cells.
The translocation of c-myc on chromosome (chr.) 15 to an immunoglobulin heavy-chain switch region on chr. 12 is the critical oncogenic step in pristane-induced plasmacytoma (PCT) development in BALB/cAnPt mice. Applying a recently developed PCR method, we have been able to detect the most commonly occurring illegitimate recombinations between alpha-chain switch region (S alpha) and c-myc in preneoplastic B cells residing in mesenteric oil granuloma (OG) tissues 7-30 days postpristane. In this study, we compare the nucleotide sequences at the S alpha/c-myc breaksites on both the c-myc-activating chr. 12+ and the reciprocal chr. 15- from eight transplanted PCTs, seven primary PCTs, and five OGs that contained six B-cell clones. These junction sequences revealed a remarkable diversity of S alpha/c-myc recombinations. In nine cases--four PCTs and five B-cell clones--nearly precise reciprocal exchanges with a loss of only 3-35 bp in c-myc were found. Large deletions in c-myc that removed 369-878 bp were observed in seven PCTs but not in early B cells. Duplications of c-myc ranging from 103 to 229 bp were also restricted to PCTs and noticed in four cases. Clonally related but different reciprocal recombinations, 38 bp apart on chr. 12+ and 15 bp apart on chr. 15-, were isolated from two different specimens of the same OG tissue from a BALB/c mouse 30 days postpristane. A second OG from another 30-day mouse yielded four recombinational fragments--two clonally related chr. 12(+)-specific fragments and two chr. 15(-)-specific fragments--one of which carried a 143-bp insertion of a microsatellite at the breaksite. We suggest that the initial recombinational break-point regions between S alpha and c-myc in plasmacytoma precursor cells at the time of immunoglobulin heavy-chain switching are intrinsically labile and characterized by a persisting instability of c-myc, which can result in large secondary deletions of c-myc.
Müller
J R
JR
Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Potter
M
M
Janz
S
S
D000818:Animals; D001402:B-Lymphocytes; D001483:Base Sequence; D002273:Carcinogens; D002874:Chromosome Mapping; D017931:DNA Primers; D005812:Genes, Switch; D016259:Genes, myc; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010954:Plasmacytoma / Q000139:chemically induced / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics; D011995:Recombination, Genetic; D017384:Sequence Deletion; D013729:Terpenes / Q000633:toxicity; D014178:Translocation, Genetic
D002273:Carcinogens; D017931:DNA Primers; D007143:Immunoglobulin Heavy Chains; D013729:Terpenes; C009042:pristane