RETROVIRAL ENHANCER INSERTION 5' OF C-MYC IN 2 TRANSLOCATION-NEGATIVEMOUSE PLASMACYTOMAS UP-REGULATES C-MYC EXPRESSION TO DIFFERENT EXTENTS

Essentially all murine plasmacytomas have deregulated c-myc expression that is typically brought about by chromosomal translocations between the c-myc/Pvt-1 locus and one of the immunoglobulin loci. ABPC 22 and RFPC 2782 are BALB/c plasmacytomas that lack chromosomal translocatio ns yet have Southern blot evidence of c-myc gene rearrangements. In th is report we show that proviral integrations 5' of the c-myc gene can deregulate c-myc expression in mouse plasmacytomas. Analysis of DNA se quences 5' of the c-myc genes from both tumors demonstrated that rearr angements were caused by retroviral integrations 5' of c-myc exon 1. T he proviral insertion in RFPC 2782 was associated with a high steady-s tate c-myc mRNA level comparable to that seen in plasmacytomas with ty pical translocations. An analogous proviral insertion in ABPC 22 was a ssociated with a c-myc RNA level that was only 38% of that of RFPC 278 2. Nuclear run-on studies of c-myc transcription showed that ABPC 22 h as both a lower rate of transcription and a greater degree of transcri ptional attenuation than RFPC 2782. DNA sequencing of the long termina l repeat of each tumor provirus showed that the ABPC 22 provirus harbo rs a deletion of one of the two direct repeats in the viral enhancer, whereas both repeats are present in the RFPC 2782 provirus. These data indicate that maximum LTR enhancer effectiveness in plasmacytomas in vivo requires the presence of both LTR direct repeats. The documentati on of the low level of steady-state c-myc mRNA in ABPC 22 supports the notion that deregulated c-myc expression, even at low steady state le vels, is effective in supporting the development of plasmacytomas.