Variable IgH chain enhancer activity in Burkitt's lymphomas suggests an additional, direct mechanism of c-myc...

The deregulation of the c-myc gene in small non-cleaved cell lymphomas (SNCL) with 8;14 translocations is thought to be due to the juxtaposition of this gene with the IgH chain locus, but exactly how the Ig locus contributes to the deregulation is unclear. One widely considered hypothesis is that Ig gene enhancers, when moved near c-myc, might stimulate inappropriate transcription of this gene. To evaluate this hypothesis, we have tested the ability of the two known H chain enhancers, the JH-C mu intronic enhancer and the 3' alpha enhancer, to support transcription from c-myc promoters, by using transient transfection assays in a panel of 32 SNCL cell lines with 8;14 translocations. The activity of the JH-C mu intronic enhancer varied widely among the cell lines tested and correlated with the presence of nuclear factors binding to the E4/octamer regions of the enhancer. The 3' alpha enhancer was much less active than the intronic enhancer in all of our cell lines and seems unlikely to account for the c-myc deregulation (although the enhancer we tested was from the rat, because the human homologue is unidentified at present). A marked difference was also seen in the ability of individual cell lines to support transcription from the unenhanced c-myc constructs. Cell lines supporting the lowest enhancer activity tended to support the highest level of transcription from unenhanced c-myc promoters. The differences in transcription from c-myc promoters were confirmed by stably transfecting constructs containing c-myc promoters in SNCL cell lines. Our data strongly suggest that the importance of Ig enhancers for c-myc deregulation varies markedly in different cell lines and that, for many, trans-acting regulators of the c-myc promoters are as important or more important, than Ig enhancers in the deregulation of the c-myc gene.