Long-distance activation of the Myc protooncogene by provirus insertion in Mlvi-1 or Mlvi-4 in rat T-cell lymphomas.

Abstract

T-cell lymphomas induced by Moloney murine leukemia virus frequently have proviruses integrated at the Mlvi-4 and Mlvi-l loci, which map approximately 30 and 270 kilobases 3' of the promoter region of the Myc protooncogene, respectively. Provirus insertion in these loci is responsible for the activation of adjacent genes. To determine whether Myc expression was also affected by these provirus insertions, we constructed T-cell hybrids between two rat thymic lymphomas containing a provirus in Mlvi-4 or Mlvi-I and the murine T-cell lymphoma line BW5147. These hybrids segregated the provirus-containing rearranged alleles from the normal nonrearranged alleles of Mlvi-4 and Mlvi-), and they carried an intact copy of rat Myc. Using an S1 nuclease protection assay, we observed that the expression of the rat Myc cosegregated with the rearranged Mlvi-4 or Mlvi-I locus. However, provirus insertion in these loci had no effect on promoter utilization or on the expression of the murine Myc locus. We conclude that provirus insertion exerts a long-range cis effect on the expression of Myc. Therefore, provirus integration in a single locus may affect the expression of multiple genes, some of which may be located a long distance from the site of integration.

What retroviruses teach us about the involvement of c-Myc in leukemias and lymphomas

“…60 Insertion of MuLV enhancers up to 300 kb distal to the cMyc promoters has been reported to give c-Myc overexpression. 85,86 Long distance effects on c-Myc expression had been suggested previously from mapping of chromosome translocation breakpoints found in human B cell and T cell lymphomas. 25,87 Because retroviral enhancers can influence oncogene expression over long distances, it is also possible that integration near c-Myc affects other genes in the vicinity.…”

“…89 In normal murine thymus, the P2 promoter is predominant, whereas the average P1/P2 promoter usage was 1.2 in MCF-induced lymphomas. 68 The Moloney MuLV-infected rat thymomas examined by Lazo et al 85 did not show a P1 to P2 promoter shift, so shifts in promoter usage are not an invariable consequence of MuLV integrations. However, since the integrations described in the rat thymomas appear to be at considerable distances from the cMyc promoters, these insertions may be less likely to affect promoter utilization.…”

“…These data indicated that the effect of the integrations was cis-acting, and that the proviral insertions did not indirectly activate a transcription factor that could upregulate c-Myc expression. 85 However, it remains possible that some of these rat thymomas had undetected Moloney insertions closer to c-Myc than those observed at Mlvi1 and Mlvi4, and that these more c-Myc-proximal integrations were responsible for elevation of proto-oncogene levels. In any event, these experiments suggest that retroviral enhancers can act at considerable distances to activate c-Myc.…”

“…To determine if c-Myc was activated by retroviral insertions at the Mlvi1 or Mlvi4 sites, Lazo et al 85 created hybrids between the uninfected mouse leukemia line BW5147 and each of two rat lymphomas induced by Moloney MuLV, one containing an integration in Mlvi1 and the other in Mlvi4. After fusion, the T cell hybrids were characterized for the segregation of chromosomes containing the integration vs those containing the unrearranged allele.…”

“…Studies using retroviruses in animal model systems suggest that juxtaposition of the c-Myc gene to a novel enhancer, even over long distances, is sufficient to give proto-oncogene deregulation. 85 The validity of this assumption is borne out by observations that many human leukemias involve c-myc translocations that probably place novel cellular regulatory elements nearby. [16][17][18][19] Because retroviruses have self-contained and mobile enhancers, dissection of these enhancers is often much further advanced than those involving cellular genes.…”