Genomic instability in B-cells and diversity of recombinations that activate c-myc.
Genetic rearrangements activating the proto-oncogene c-myc comprise a mandatory oncogenic step in plasma cell tumor development in BALB/cAnPt mice. In the majority of plasmacytomas, c-myc activating rearrangements take the form of reciprocal chromosomal translocations t(12;15) that juxtapose c-myc to the immunoglobulin heavy chain alpha locus (IgH alpha) in particular the switch alpha region (S alpha). The genetic basis for the prevalence of S alpha/c-myc recombinations in BALB/cAnPt plasmacytomas is not known but may be related to a hypothetical regional genomic instability of the c-myc and IgH alpha loci in BALB/cAnPt mice. We wished to test whether the genomic instability of both loci might be revealed by the diversity of genetic recombinations that can be observed in IgH alpha and c-myc. We employed PCR methods to detect new recombinations of c-myc and IgH alpha in the preneoplastic stage of plasma cell tumor development and found that c-myc can be joined to more genes or genomic regions than known before. This is indicative but does not formally prove a particular genomic instability of c-myc and IgH alpha in BALB/cAnPt B cells. Since defective DNA repair provides a mechanistic explanation for genomic instability, we measured the efficiency of repair in IgH alpha and c-myc using an assay that quantitates the removal of UV-induced pyrimidine dimers within specific genomic regions. We used plasmacytoma XRPC 24 as a model system and found that both IgH alpha and c-myc were poorly repaired, whereas c-abl, a proto-oncogene not related to conventional pristane-induced plasmacytoma-genesis, was efficiently repaired.
Janz
S
S
Laboratory of Genetics, NCI, NIH.
Jones
G M
GM
Müller
J R
JR
Potter
M
M
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D005786:Gene Expression Regulation; D015322:Gene Rearrangement, B-Lymphocyte; D005812:Genes, Switch; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D006099:Granuloma / Q000139:chemically induced / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010538:Peritonitis / Q000139:chemically induced / Q000235:genetics; D010954:Plasmacytoma / Q000139:chemically induced / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics*; D011995:Recombination, Genetic; D013729:Terpenes / Q000633:toxicity; D014178:Translocation, Genetic
D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D013729:Terpenes; C009042:pristane