Analysis of wild-type and mutant SL3-3 murine leukemia virus insertions in the c-myc promoter during lymphomagenesis reveals target site hot spots, virus-dependent patterns, and frequent error-prone gap repair.
The murine leukemia retrovirus SL3-3 induces lymphomas in the T-cell compartment of the hematopoetic system when it is injected into newborn mice of susceptible strains. Previously, our laboratory reported on a deletion mutant of SL3-3 that induces T-cell tumors faster than the wild-type virus (S. Ethelberg, A. B. Sorensen, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:9796-9799, 1997). PCR analyses of proviral integrations in the promoter region of the c-myc proto-oncogene in lymphomas induced by wild-type SL3-3 [SL3-3(wt)] and the enhancer deletion mutant displayed a difference in targeting frequency into this locus. We here report on patterns of proviral insertions into the c-myc promoter region from SL3-3(wt), the faster variant, as well as other enhancer variants from a total of approximately 250 tumors. The analysis reveals (i) several integration site hot spots in the c-myc promoter region, (ii) differences in integration patterns between SL3-3(wt) and enhancer deletion mutant viruses, (iii) a correlation between tumor latency and the number of proviral insertions into the c-myc promoter, and (iv) a [5'-(A/C/G)TA(C/G/T)-3'] integration site consensus sequence. Unexpectedly, about 12% of the sequenced insertions were associated with point mutations in the direct repeat flanking the provirus. Based on these results, we propose a model for error-prone gap repair of host-provirus junctions.
Nielsen
Anne Ahlmann
AA
Department of Molecular Biology, University of Aarhus, Aarhus, Denmark.
Sørensen
Annette Balle
AB
Schmidt
Jörg
J
Pedersen
Finn Skou
FS
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D016384:Consensus Sequence; D004260:DNA Repair; D004742:Enhancer Elements, Genetic; D005260:Female; D017353:Gene Deletion; D016259:Genes, myc; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000472:pathogenicity*; D007942:Leukemia, Experimental / Q000473:pathology / Q000821:virology; D016399:Lymphoma, T-Cell / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011533:Proviruses / Q000235:genetics*; D012192:Retroviridae Infections / Q000473:pathology / Q000821:virology; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology; D016662:Virus Integration / Q000235:genetics*
D016271:Proto-Oncogene Proteins c-myc