Eμ/Sμ transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells

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Abstract
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 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, and a truncated switch region, S, were found in the first intron of Myc in lymph node cells of IL-6 transgenic BALB/c mice. In two cases E/S transposition primed Myc to get involved in apparent trans-chromosomal CSR to C1, presumably leading to T(12;15). Translocations preceded by E/S 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/S 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 enhancer, which appears to be required for deregulating Myc in a manner that is conducive to PCT development.