E mu/S mu transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells.
Misguided immunoglobulin (Ig) class switch recombination (CSR) has been implicated in the origin of Myc-activating chromosomal translocations, T(12;15), in BALB/c mouse plasmacytomas (PCTs). CSR has also been involved in the progression of T(12;15); for example, the approximation of Myc to the 3'-C alpha enhancer. This study provides evidence for an additional mechanism by which aberrant CSR may facilitate T(12;15): transposition of Ig heavy-chain (IgH) sequences to Myc. Five IgH transposons containing the intronic heavy-chain enhancer, E mu, and a truncated switch mu region, S mu, were found in the first intron of Myc in lymph node cells of IL-6 transgenic BALB/c mice. In two cases E mu/S mu transposition primed Myc to get involved in apparent trans-chromosomal CSR to C gamma 1, presumably leading to T(12;15). Translocations preceded by E mu/S mu transposition can sometimes be distinguished from de novo translocations by molecular fingerprints in translocation breakpoint regions (Ig switch region [S] inversions and unusual gene orders in composite S regions). The presence of such fingerprints in some PCTs suggests that the tumors sometimes evolve from transposition-bearing precursors. We propose that E mu/S mu transposition to Myc may facilitate plasmacytomagenesis by sensitizing Myc to undergo T(12;15) translocation. T(12;15), in turn, juxtaposes Myc to the 3'-C alpha enhancer, which appears to be required for deregulating Myc in a manner that is conducive to PCT development.
Kovalchuk
Alexander L
AL
Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Kim
Joong Su
JS
Janz
Siegfried
S
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001483:Base Sequence; D002874:Chromosome Mapping; D017931:DNA Primers; D004251:DNA Transposable Elements; D016259:Genes, myc; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D014178:Translocation, Genetic
D017931:DNA Primers; D004251:DNA Transposable Elements; D007143:Immunoglobulin Heavy Chains