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. 1985 Oct;56(1):258–267. doi: 10.1128/jvi.56.1.258-267.1985

Concerted DNA rearrangements in Moloney murine leukemia virus-induced thymomas: a potential synergistic relationship in oncogenesis.

P N Tsichlis, P G Strauss, M A Lohse
PMCID: PMC252516  PMID: 2993654

Abstract

Rat thymic lymphomas induced by Moloney murine leukemia virus carry DNA rearrangements due to provirus integration in at least five independent cellular DNA domains (Mlvi-1, Mlvi-2, Mlvi-3, RMoInt-1, and c-myc). We had previously shown that rearrangements in more than one of these domains could occur in the same tumor. In this report we extend these findings by showing that, with one exception, tumors containing provirus insertions in Mlvi-1 always contained provirus insertions in a second locus, Mlvi-2. To determine whether both events occurred in the same population of tumor cells, we examined the clonal nature of these tumors by taking advantage of allelic polymorphisms that occur naturally in both Mlvi-1 and Mlvi-2. Tumors with provirus insertions in both Mlvi-1 and Mlvi-2 arising in rats heterozygous at one of these loci were identified. DNA from these tumors was analyzed by restriction endonuclease digestion and hybridization to DNA probes derived from both Mlvi-1 and Mlvi-2. Thus, we determined the clonal nature of three thymomas and showed that in these tumors both insertion events occurred in the same population of tumor cells. The concomitant appearance of provirus insertions in Mlvi-1 and Mlvi-2 suggests a synergism of these two events that may be important in tumor induction and progression.

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Selected References

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  1. 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]
  2. Cooper G. M., Lane M. A. Cellular transforming genes and oncogenesis. Biochim Biophys Acta. 1984;738(1-2):9–20. doi: 10.1016/0304-419x(84)90017-9. [DOI] [PubMed] [Google Scholar]
  3. Corcoran L. M., Adams J. M., Dunn A. R., Cory S. Murine T lymphomas in which the cellular myc oncogene has been activated by retroviral insertion. Cell. 1984 May;37(1):113–122. doi: 10.1016/0092-8674(84)90306-4. [DOI] [PubMed] [Google Scholar]
  4. Cuypers H. T., Selten G., Quint W., Zijlstra M., Maandag E. R., Boelens W., van Wezenbeek P., Melief C., Berns A. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell. 1984 May;37(1):141–150. doi: 10.1016/0092-8674(84)90309-x. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Economou-Pachnis A., Lohse M. A., Furano A. V., Tsichlis P. N. Insertion of long interspersed repeated elements at the Igh (immunoglobulin heavy chain) and Mlvi-2 (Moloney leukemia virus integration 2) loci of rats. Proc Natl Acad Sci U S A. 1985 May;82(9):2857–2861. doi: 10.1073/pnas.82.9.2857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fung Y. K., Lewis W. G., Crittenden L. B., Kung H. J. Activation of the cellular oncogene c-erbB by LTR insertion: molecular basis for induction of erythroblastosis by avian leukosis virus. Cell. 1983 Jun;33(2):357–368. doi: 10.1016/0092-8674(83)90417-8. [DOI] [PubMed] [Google Scholar]
  8. Grégoire D., Couez D., Deschamps J., Heuertz S., Hors-Cayla M. C., Szpirer J., Szpirer C., Burny A., Huez G., Kettmann R. Different bovine leukemia virus-induced tumors harbor the provirus in different chromosomes. J Virol. 1984 Apr;50(1):275–279. doi: 10.1128/jvi.50.1.275-279.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Haseltine W. A., Sodroski J., Patarca R., Briggs D., Perkins D., Wong-Staal F. Structure of 3' terminal region of type II human T lymphotropic virus: evidence for new coding region. Science. 1984 Jul 27;225(4660):419–421. doi: 10.1126/science.6330894. [DOI] [PubMed] [Google Scholar]
  10. Hayward W. S., Neel B. G., Astrin S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature. 1981 Apr 9;290(5806):475–480. doi: 10.1038/290475a0. [DOI] [PubMed] [Google Scholar]
  11. Karn J., Brenner S., Barnett L., Cesareni G. Novel bacteriophage lambda cloning vector. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5172–5176. doi: 10.1073/pnas.77.9.5172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kettmann R., Deschamps J., Cleuter Y., Couez D., Burny A., Marbaix G. Leukemogenesis by bovine leukemia virus: proviral DNA integration and lack of RNA expression of viral long terminal repeat and 3' proximate cellular sequences. Proc Natl Acad Sci U S A. 1982 Apr;79(8):2465–2469. doi: 10.1073/pnas.79.8.2465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klein G. Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men. Cell. 1983 Feb;32(2):311–315. doi: 10.1016/0092-8674(83)90449-x. [DOI] [PubMed] [Google Scholar]
  14. Krontiris T. G., Cooper G. M. Transforming activity of human tumor DNAs. Proc Natl Acad Sci U S A. 1981 Feb;78(2):1181–1184. doi: 10.1073/pnas.78.2.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Laimins L. A., Tsichlis P., Khoury G. Multiple enhancer domains in the 3' terminus of the Prague strain of Rous sarcoma virus. Nucleic Acids Res. 1984 Aug 24;12(16):6427–6442. doi: 10.1093/nar/12.16.6427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
  17. Lemay G., Jolicoeur P. Rearrangement of a DNA sequence homologous to a cell-virus junction fragment in several Moloney murine leukemia virus-induced rat thymomas. Proc Natl Acad Sci U S A. 1984 Jan;81(1):38–42. doi: 10.1073/pnas.81.1.38. [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., 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]
  20. Mullins J. I., Brody D. S., Binari R. C., Jr, Cotter S. M. Viral transduction of c-myc gene in naturally occurring feline leukaemias. 1984 Apr 26-May 2Nature. 308(5962):856–858. doi: 10.1038/308856a0. [DOI] [PubMed] [Google Scholar]
  21. Neil J. C., Hughes D., McFarlane R., Wilkie N. M., Onions D. E., Lees G., Jarrett O. Transduction and rearrangement of the myc gene by feline leukaemia virus in naturally occurring T-cell leukaemias. 1984 Apr 26-May 2Nature. 308(5962):814–820. doi: 10.1038/308814a0. [DOI] [PubMed] [Google Scholar]
  22. Noori-Daloii M. R., Swift R. A., Kung H. J., Crittenden L. B., Witter R. L. Specific integration of REV proviruses in avian bursal lymphomas. Nature. 1981 Dec 10;294(5841):574–576. doi: 10.1038/294574a0. [DOI] [PubMed] [Google Scholar]
  23. Nusse R., Varmus H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982 Nov;31(1):99–109. doi: 10.1016/0092-8674(82)90409-3. [DOI] [PubMed] [Google Scholar]
  24. Nusse R., van Ooyen A., Cox D., Fung Y. K., Varmus H. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature. 1984 Jan 12;307(5947):131–136. doi: 10.1038/307131a0. [DOI] [PubMed] [Google Scholar]
  25. Payne G. S., Bishop J. M., Varmus H. E. Multiple arrangements of viral DNA and an activated host oncogene in bursal lymphomas. Nature. 1982 Jan 21;295(5846):209–214. doi: 10.1038/295209a0. [DOI] [PubMed] [Google Scholar]
  26. Payne G. S., Courtneidge S. A., Crittenden L. B., Fadly A. M., Bishop J. M., Varmus H. E. Analysis of avian leukosis virus DNA and RNA in bursal tumours: viral gene expression is not required for maintenance of the tumor state. Cell. 1981 Feb;23(2):311–322. doi: 10.1016/0092-8674(81)90127-6. [DOI] [PubMed] [Google Scholar]
  27. Perucho M., Goldfarb M., Shimizu K., Lama C., Fogh J., Wigler M. Human-tumor-derived cell lines contain common and different transforming genes. Cell. 1981 Dec;27(3 Pt 2):467–476. doi: 10.1016/0092-8674(81)90388-3. [DOI] [PubMed] [Google Scholar]
  28. Peters G., Brookes S., Smith R., Dickson C. Tumorigenesis by mouse mammary tumor virus: evidence for a common region for provirus integration in mammary tumors. Cell. 1983 Jun;33(2):369–377. doi: 10.1016/0092-8674(83)90418-x. [DOI] [PubMed] [Google Scholar]
  29. Pulciani S., Santos E., Lauver A. V., Long L. K., Robbins K. C., Barbacid M. Oncogenes in human tumor cell lines: molecular cloning of a transforming gene from human bladder carcinoma cells. Proc Natl Acad Sci U S A. 1982 May;79(9):2845–2849. doi: 10.1073/pnas.79.9.2845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rice N. R., Stephens R. M., Couez D., Deschamps J., Kettmann R., Burny A., Gilden R. V. The nucleotide sequence of the env gene and post-env region of bovine leukemia virus. Virology. 1984 Oct 15;138(1):82–93. doi: 10.1016/0042-6822(84)90149-1. [DOI] [PubMed] [Google Scholar]
  31. Ruley H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. doi: 10.1038/304602a0. [DOI] [PubMed] [Google Scholar]
  32. Seiki M., Eddy R., Shows T. B., Yoshida M. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells. Nature. 1984 Jun 14;309(5969):640–642. doi: 10.1038/309640a0. [DOI] [PubMed] [Google Scholar]
  33. Shih C., Padhy L. C., Murray M., Weinberg R. A. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature. 1981 Mar 19;290(5803):261–264. doi: 10.1038/290261a0. [DOI] [PubMed] [Google Scholar]
  34. Shinnick T. M., Lerner R. A., Sutcliffe J. G. Nucleotide sequence of Moloney murine leukaemia virus. Nature. 1981 Oct 15;293(5833):543–548. doi: 10.1038/293543a0. [DOI] [PubMed] [Google Scholar]
  35. Sodroski J. G., Rosen C. A., Haseltine W. A. Trans-acting transcriptional activation of the long terminal repeat of human T lymphotropic viruses in infected cells. Science. 1984 Jul 27;225(4660):381–385. doi: 10.1126/science.6330891. [DOI] [PubMed] [Google Scholar]
  36. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  37. Steffen D. Proviruses are adjacent to c-myc in some murine leukemia virus-induced lymphomas. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2097–2101. doi: 10.1073/pnas.81.7.2097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tsichlis P. N., Coffin J. M. Recombinants between endogenous and exogenous avian tumor viruses: role of the C region and other portions of the genome in the control of replication and transformation. J Virol. 1980 Jan;33(1):238–249. doi: 10.1128/jvi.33.1.238-249.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tsichlis P. N., Coffin J. M. Role of the C region in relative growth rates of endogenous and exogenous avian oncoviruses. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 2):1123–1132. doi: 10.1101/sqb.1980.044.01.121. [DOI] [PubMed] [Google Scholar]
  40. Tsichlis P. N., Donehower L., Hager G., Zeller N., Malavarca R., Astrin S., Skalka A. M. Sequence comparison in the crossover region of an oncogenic avian retrovirus recombinant and its nononcogenic parent: genetic regions that control growth rate and oncogenic potential. Mol Cell Biol. 1982 Nov;2(11):1331–1338. doi: 10.1128/mcb.2.11.1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tsichlis P. N., Strauss P. G., Hu L. F. A common region for proviral DNA integration in MoMuLV-induced rat thymic lymphomas. 1983 Mar 31-Apr 6Nature. 302(5907):445–449. doi: 10.1038/302445a0. [DOI] [PubMed] [Google Scholar]
  42. Tsichlis P. N., Strauss P. G., Kozak C. A. Cellular DNA region involved in induction of thymic lymphomas (Mlvi-2) maps to mouse chromosome 15. Mol Cell Biol. 1984 May;4(5):997–1000. doi: 10.1128/mcb.4.5.997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wachsman W., Shimotohno K., Clark S. C., Golde D. W., Chen I. S. Expression of the 3' terminal region of human T-cell leukemia viruses. Science. 1984 Oct 12;226(4671):177–179. doi: 10.1126/science.6091270. [DOI] [PubMed] [Google Scholar]

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