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Journal of Virology, January 2009, p. 336-346, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01368-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Control of Pathogenicity and Disease Specificity of a T-Lymphomagenic Gammaretrovirus by E-Box Motifs but Not by an Overlapping Glucocorticoid Response Element{triangledown}

Ditte Ejegod,1 Karina Dalsgaard Sørensen,1 Ilona Mossbrugger,2 Leticia Quintanilla-Martinez,2 Jörg Schmidt,3 and Finn Skou Pedersen1*

Department of Molecular Biology, University of Aarhus, Denmark,1 Institute of Pathology,2 Department of Comparative Medicine, Helmholtz Zentrum Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany3

Received 1 July 2008/ Accepted 13 October 2008

Although transcription factors of the basic helix-loop-helix family have been shown to regulate enhancers of lymphomagenic gammaretroviruses through E-box motifs, the overlap of an E-box motif (Egre) with the glucocorticoid response element (GRE) has obscured their function in vivo. We report here 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 backup site for Egre. While wild-type SL3-3 and GRE and Ea/s mutants exclusively induced T-cell lymphomas with wild-type latencies mainly of the CD4+ CD8– phenotype, Egre as well as the Egre and 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 wild-type SL3-3, indicating the incomplete disruption of T-cell lymphomagenesis, which is in contrast to previous findings for a Runx site mutant of SL3-3. Mutating the Egre site or Egre and Ea/s triggered several tumor phenotype-associated secondary enhancer changes encompassing neighboring sites, none of which led to the regeneration of an E-box motif. Taken together, 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.

* Corresponding author. Mailing address: Department of Molecular Biology, University of Aarhus, C. F. Møllers Alle, bldg. 130, DK-8000 Aarhus, Denmark. Phone: 4589422614. Fax: 4586196500. E-mail: fsp{at}mb.au.dk

{triangledown} Published ahead of print on 22 October 2008.

Journal of Virology, January 2009, p. 336-346, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01368-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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