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Finn Skou Pedersen

Control of pathogenicity and disease specificity of a T-lymphomagenic gammaretrovirus by E-box motifs but not by an overlapping glucocorticoid response element

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  • Ditte Ejegod, Denmark
  • Karina Dalsgaard Sørensen
  • Ilona Moßbrugger, Helmholtz Zentrum München, Germany
  • Leticia Quintanilla-Martinez, Helmholtz Zentrum München, Germany
  • Jörg Schmidt, Helmholtz Zentrum München, Germany
  • Finn Skou Pedersen
  • Department of Molecular Biology
  • Interdisciplinary Nanoscience Center
Although transcription factors of the basic-helix-loop-helix family have been shown to regulate enhancers of lymphomagenic gammaretroviruses through E-box motifs, overlap of an E-box motif (Egre) with the glucocorticoid response element (GRE) has obscured their function in vivo. We here report that Egre, but not the GRE affects disease induction by the murine T-lymphomagenic SL3-3 virus. Mutating all three copies of Egre prolonged the tumor latency period from 60 to 109 days. Further mutating an E-box motif (Ea/s) outside the enhancer prolonged the latency period to 180 days, suggesting that Ea/s works as a back-up site for Egre. While SL3-3 wt, GRE and Ea/s mutants induced exclusively T-cell lymphomas with wild type latencies, mainly of the CD4+CD8- phenotype, the Egre as well as the Egre plus Ea/s mutants induced B-cell lymphomas and myeloid leukemia in addition to T-cell lymphomas. T-cell lymphomas induced by the two Egre mutants had the same phenotype as those induced by SL3-3 wt, indicating incomplete disruption of T-cell lymphomagenesis in contrast to previous findings for a Runx site mutant of SL3-3. Mutating the Egre site or Egre plus Ea/s triggered several tumor phenotype-associated secondary enhancer changes encompassing neighboring sites, none of which led to regeneration of an E-box motif. Altogether, our results demonstrate a role for the E-box, but not the GRE in T-lymphomagenesis by SL3-3, unveil an inherent broader disease specificity of the virus, and strengthen the notion of selection for more potent enhancer variants of mutated viruses during tumor development.
Original languageEnglish
JournalJournal of Virology
Pages (from-to)336-346
Number of pages11
Publication statusPublished - 2009

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