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. 1997 Feb;71(2):1213–1219. doi: 10.1128/jvi.71.2.1213-1219.1997

Importance of a c-Myb binding site for lymphomagenesis by the retrovirus SL3-3.

A Nieves 1, L S Levy 1, J Lenz 1
PMCID: PMC191175  PMID: 8995644

Abstract

All murine leukemia viruses (MuLVs) and related type C retroviruses contain a highly conserved binding site for the Ets family of transcription factors within the enhancer sequences in the viral long terminal repeats (LTRs). The T-cell lymphomagenic MuLV SL3-3 (SL3-3) also contains a c-Myb binding site adjacent to the Ets site. The presence of this Myb site distinguishes SL3 from most other MuLVs. We tested the importance of these two sites for the lymphomagenicity of SL3-3. Mutation of the Ets site had little effect on viral pathogenicity, as it only slightly extended the latency period to disease onset. In contrast, mutation of the Myb site strongly inhibited pathogenicity, as only a minority of the inoculated mice developed tumors in the two mouse strains that were tested. All tumors that were induced by either mutant appeared to be lymphomas, and no evidence for reversion of either mutation was detected. The effects of the Ets and Myb site mutations on transcriptional activity of the SL3 LTR were tested by inserting the viral enhancer sequences into a plasmid containing the promoter region of the c-myc gene linked to a reporter gene. Mutation the Myb site almost eliminated enhancer activity in T lymphocytes, while mutation of the Ets site had smaller effects. Thus, the effects of the enhancer mutations on transcriptional activity in T cells paralleled their effects on viral lymphomagenicity. The absence of the c-Myb site in the LTR enhancer of the weakly lymphomagenic MuLV, Akv, likely contributes to the low pathogenicity of this virus relative to SL3-3. However, Moloney MuLV also lacks the Myb site in its LTR, although it induces T-cell lymphomas with a potency similar to that of SL3-3. Thus, it appears that SL3-3 and Moloney MuLV evolved genetic determinants of T-cell lymphomagenicity that are, at least in part, distinct.

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Selected References

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  1. Athas G. B., Choi B., Prabhu S., Lobelle-Rich P. A., Levy L. S. Genetic determinants of feline leukemia virus-induced multicentric lymphomas. Virology. 1995 Dec 20;214(2):431–438. doi: 10.1006/viro.1995.0053. [DOI] [PubMed] [Google Scholar]
  2. Bae S. C., Yamaguchi-Iwai Y., Ogawa E., Maruyama M., Inuzuka M., Kagoshima H., Shigesada K., Satake M., Ito Y. Isolation of PEBP2 alpha B cDNA representing the mouse homolog of human acute myeloid leukemia gene, AML1. Oncogene. 1993 Mar;8(3):809–814. [PubMed] [Google Scholar]
  3. Boral A. L., Okenquist S. A., Lenz J. Identification of the SL3-3 virus enhancer core as a T-lymphoma cell-specific element. J Virol. 1989 Jan;63(1):76–84. doi: 10.1128/jvi.63.1.76-84.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brightman B. K., Rein A., Trepp D. J., Fan H. An enhancer variant of Moloney murine leukemia virus defective in leukemogenesis does not generate detectable mink cell focus-inducing virus in vivo. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2264–2268. doi: 10.1073/pnas.88.6.2264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Celander D., Haseltine W. A. Glucocorticoid regulation of murine leukemia virus transcription elements is specified by determinants within the viral enhancer region. J Virol. 1987 Feb;61(2):269–275. doi: 10.1128/jvi.61.2.269-275.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chatis P. A., Holland C. A., Hartley J. W., Rowe W. P., Hopkins N. Role for the 3' end of the genome in determining disease specificity of Friend and Moloney murine leukemia viruses. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4408–4411. doi: 10.1073/pnas.80.14.4408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chatis P. A., Holland C. A., Silver J. E., Frederickson T. N., Hopkins N., Hartley J. W. A 3' end fragment encompassing the transcriptional enhancers of nondefective Friend virus confers erythroleukemogenicity on Moloney leukemia virus. J Virol. 1984 Oct;52(1):248–254. doi: 10.1128/jvi.52.1.248-254.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Corneliussen B., Thornell A., Hallberg B., Grundström T. Helix-loop-helix transcriptional activators bind to a sequence in glucocorticoid response elements of retrovirus enhancers. J Virol. 1991 Nov;65(11):6084–6093. doi: 10.1128/jvi.65.11.6084-6093.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DesGroseillers L., Jolicoeur P. The tandem direct repeats within the long terminal repeat of murine leukemia viruses are the primary determinant of their leukemogenic potential. J Virol. 1984 Dec;52(3):945–952. doi: 10.1128/jvi.52.3.945-952.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DesGroseillers L., Rassart E., Jolicoeur P. Thymotropism of murine leukemia virus is conferred by its long terminal repeat. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4203–4207. doi: 10.1073/pnas.80.14.4203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Golemis E. A., Speck N. A., Hopkins N. Alignment of U3 region sequences of mammalian type C viruses: identification of highly conserved motifs and implications for enhancer design. J Virol. 1990 Feb;64(2):534–542. doi: 10.1128/jvi.64.2.534-542.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Golemis E., Li Y., Fredrickson T. N., Hartley J. W., Hopkins N. Distinct segments within the enhancer region collaborate to specify the type of leukemia induced by nondefective Friend and Moloney viruses. J Virol. 1989 Jan;63(1):328–337. doi: 10.1128/jvi.63.1.328-337.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hallberg B., Schmidt J., Luz A., Pedersen F. S., Grundström T. SL3-3 enhancer factor 1 transcriptional activators are required for tumor formation by SL3-3 murine leukemia virus. J Virol. 1991 Aug;65(8):4177–4181. doi: 10.1128/jvi.65.8.4177-4181.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hedrick S. M., Cohen D. I., Nielsen E. A., Davis M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature. 1984 Mar 8;308(5955):149–153. doi: 10.1038/308149a0. [DOI] [PubMed] [Google Scholar]
  15. Ishimoto A., Takimoto M., Adachi A., Kakuyama M., Kato S., Kakimi K., Fukuoka K., Ogiu T., Matsuyama M. Sequences responsible for erythroid and lymphoid leukemia in the long terminal repeats of Friend-mink cell focus-forming and Moloney murine leukemia viruses. J Virol. 1987 Jun;61(6):1861–1866. doi: 10.1128/jvi.61.6.1861-1866.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kamachi Y., Ogawa E., Asano M., Ishida S., Murakami Y., Satake M., Ito Y., Shigesada K. Purification of a mouse nuclear factor that binds to both the A and B cores of the polyomavirus enhancer. J Virol. 1990 Oct;64(10):4808–4819. doi: 10.1128/jvi.64.10.4808-4819.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lawrenz-Smith S. C., Massey A. C., Innes D. J., Thomas C. Y. Pathogenic determinants in the U3 region of recombinant murine leukemia viruses isolated from CWD and HRS/J mice. J Virol. 1994 Aug;68(8):5174–5183. doi: 10.1128/jvi.68.8.5174-5183.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lenz J., Celander D., Crowther R. L., Patarca R., Perkins D. W., Haseltine W. A. Determination of the leukaemogenicity of a murine retrovirus by sequences within the long terminal repeat. 1984 Mar 29-Apr 4Nature. 308(5958):467–470. doi: 10.1038/308467a0. [DOI] [PubMed] [Google Scholar]
  19. Li Y., Golemis E., Hartley J. W., Hopkins N. Disease specificity of nondefective Friend and Moloney murine leukemia viruses is controlled by a small number of nucleotides. J Virol. 1987 Mar;61(3):693–700. doi: 10.1128/jvi.61.3.693-700.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Li Y., Holland C. A., Hartley J. W., Hopkins N. Viral integration near c-myc in 10-20% of mcf 247-induced AKR lymphomas. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6808–6811. doi: 10.1073/pnas.81.21.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. LoSardo J. E., Boral A. L., Lenz J. Relative importance of elements within the SL3-3 virus enhancer for T-cell specificity. J Virol. 1990 Apr;64(4):1756–1763. doi: 10.1128/jvi.64.4.1756-1763.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Manley N. R., O'Connell M., Sun W., Speck N. A., Hopkins N. Two factors that bind to highly conserved sequences in mammalian type C retroviral enhancers. J Virol. 1993 Apr;67(4):1967–1975. doi: 10.1128/jvi.67.4.1967-1975.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Morrison H. L., Dai H. Y., Pedersen F. S., Lenz J. Analysis of the significance of two single-base-pair differences in the SL3-3 and Akv virus long terminal repeats. J Virol. 1991 Feb;65(2):1019–1022. doi: 10.1128/jvi.65.2.1019-1022.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morrison H. L., Soni B., Lenz J. Long terminal repeat enhancer core sequences in proviruses adjacent to c-myc in T-cell lymphomas induced by a murine retrovirus. J Virol. 1995 Jan;69(1):446–455. doi: 10.1128/jvi.69.1.446-455.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nielsen A. L., Pallisgaard N., Pedersen F. S., Jørgensen P. Basic helix-loop-helix proteins in murine type C retrovirus transcriptional regulation. J Virol. 1994 Sep;68(9):5638–5647. doi: 10.1128/jvi.68.9.5638-5647.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. O'Donnell P. V., Fleissner E., Lonial H., Koehne C. F., Reicin A. Early clonality and high-frequency proviral integration into the c-myc locus in AKR leukemias. J Virol. 1985 Aug;55(2):500–503. doi: 10.1128/jvi.55.2.500-503.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ogawa E., Maruyama M., Kagoshima H., Inuzuka M., Lu J., Satake M., Shigesada K., Ito Y. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6859–6863. doi: 10.1073/pnas.90.14.6859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Reicin A., Yang J. Q., Marcu K. B., Fleissner E., Koehne C. F., O'Donnell P. V. Deregulation of the c-myc oncogene in virus-induced thymic lymphomas of AKR/J mice. Mol Cell Biol. 1986 Nov;6(11):4088–4092. doi: 10.1128/mcb.6.11.4088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rosen C. A., Haseltine W. A., Lenz J., Ruprecht R., Cloyd M. W. Tissue selectivity of murine leukemia virus infection is determined by long terminal repeat sequences. J Virol. 1985 Sep;55(3):862–866. doi: 10.1128/jvi.55.3.862-866.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rowe W. P., Pugh W. E., Hartley J. W. Plaque assay techniques for murine leukemia viruses. Virology. 1970 Dec;42(4):1136–1139. doi: 10.1016/0042-6822(70)90362-4. [DOI] [PubMed] [Google Scholar]
  31. Selten G., Cuypers H. T., Zijlstra M., Melief C., Berns A. Involvement of c-myc in MuLV-induced T cell lymphomas in mice: frequency and mechanisms of activation. EMBO J. 1984 Dec 20;3(13):3215–3222. doi: 10.1002/j.1460-2075.1984.tb02281.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Short M. K., Okenquist S. A., Lenz J. Correlation of leukemogenic potential of murine retroviruses with transcriptional tissue preference of the viral long terminal repeats. J Virol. 1987 Apr;61(4):1067–1072. doi: 10.1128/jvi.61.4.1067-1072.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Speck N. A., Baltimore D. Six distinct nuclear factors interact with the 75-base-pair repeat of the Moloney murine leukemia virus enhancer. Mol Cell Biol. 1987 Mar;7(3):1101–1110. doi: 10.1128/mcb.7.3.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Speck N. A., Renjifo B., Golemis E., Fredrickson T. N., Hartley J. W., Hopkins N. Mutation of the core or adjacent LVb elements of the Moloney murine leukemia virus enhancer alters disease specificity. Genes Dev. 1990 Feb;4(2):233–242. doi: 10.1101/gad.4.2.233. [DOI] [PubMed] [Google Scholar]
  35. Sun W., Graves B. J., Speck N. A. Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins. J Virol. 1995 Aug;69(8):4941–4949. doi: 10.1128/jvi.69.8.4941-4949.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Thornell A., Hallberg B., Grundström T. Binding of SL3-3 enhancer factor 1 transcriptional activators to viral and chromosomal enhancer sequences. J Virol. 1991 Jan;65(1):42–50. doi: 10.1128/jvi.65.1.42-50.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Thornell A., Hallberg B., Grundström T. Differential protein binding in lymphocytes to a sequence in the enhancer of the mouse retrovirus SL3-3. Mol Cell Biol. 1988 Apr;8(4):1625–1637. doi: 10.1128/mcb.8.4.1625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Weaver D., Costantini F., Imanishi-Kari T., Baltimore D. A transgenic immunoglobulin mu gene prevents rearrangement of endogenous genes. Cell. 1985 Aug;42(1):117–127. doi: 10.1016/s0092-8674(85)80107-0. [DOI] [PubMed] [Google Scholar]
  39. Wotton D., Ghysdael J., Wang S., Speck N. A., Owen M. J. Cooperative binding of Ets-1 and core binding factor to DNA. Mol Cell Biol. 1994 Jan;14(1):840–850. doi: 10.1128/mcb.14.1.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zaiman A. L., Lenz J. Transcriptional activation of a retrovirus enhancer by CBF (AML1) requires a second factor: evidence for cooperativity with c-Myb. J Virol. 1996 Aug;70(8):5618–5629. doi: 10.1128/jvi.70.8.5618-5629.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zaiman A. L., Lewis A. F., Crute B. E., Speck N. A., Lenz J. Transcriptional activity of core binding factor-alpha (AML1) and beta subunits on murine leukemia virus enhancer cores. J Virol. 1995 May;69(5):2898–2906. doi: 10.1128/jvi.69.5.2898-2906.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

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