Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1996 Apr;70(4):2095–2100. doi: 10.1128/jvi.70.4.2095-2100.1996

Moloney murine leukemia virus-induced lymphomas in p53-deficient mice: overlapping pathways in tumor development?

E W Baxter 1, K Blyth 1, L A Donehower 1, E R Cameron 1, D E Onions 1, J C Neil 1
PMCID: PMC190045  PMID: 8642629

Abstract

The effect of Moloney murine leukemia virus (MoMLV) infection was examined in mice lacking a functional p53 gene. Virus-infected p53-/- mice developed tumors significantly faster than uninfected p53-/- or virus-infected p53+/+ littermates. However, the degree of synergy between MoMLV and the p53 null genotype was weaker than the synergy between either of these and c-myc transgenes. A similar range of T-cell tumor phenotypes was represented in all p53 genotype groups, including p53-/- mice, which developed thymic lymphomas as the most common of several neoplastic diseases. Lack of p53 was associated with higher rates of metastasis and the ready establishment of tumors in tissue culture. Loss of the wild-type allele was a common feature of tumors in p53+/- mice and was complete in tumor cells in vitro, but this appeared to occur by a mechanism other than proviral insertion at the wild-type allele. A lower average MoMLV proviral copy number was observed in tumors of the p53 null and heterozygote groups, suggesting that the absence of a functional p53 gene reduced the number of steps required to complete the malignant phenotype. Mink cell focus-forming virus-like proviruses were detected in tumors of all infected mice but were relatively rare in p53 null mice. Analysis of c-myc, pim-1, and pal-1 showed that these loci were occupied by proviruses in some cases but at similar frequencies in p53 wild-type and null mice. In conclusion, while inactivation of p53 in the germ line predisposes mice to tumors similar in phenotype to those induced by MoMLV, it appears that virus-induced tumors generally occur without p53 loss. We speculate that a bcl-2-like function carried or induced by MoMLV may underlie this p53-independent pathway.

Full Text

The Full Text of this article is available as a PDF (298.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acton D., Domen J., Jacobs H., Vlaar M., Korsmeyer S., Berns A. Collaboration of pim-1 and bcl-2 in lymphomagenesis. Curr Top Microbiol Immunol. 1992;182:293–298. doi: 10.1007/978-3-642-77633-5_36. [DOI] [PubMed] [Google Scholar]
  2. Ben David Y., Prideaux V. R., Chow V., Benchimol S., Bernstein A. Inactivation of the p53 oncogene by internal deletion or retroviral integration in erythroleukemic cell lines induced by Friend leukemia virus. Oncogene. 1988 Aug;3(2):179–185. [PubMed] [Google Scholar]
  3. Bergeron D., Houde J., Poliquin L., Barbeau B., Rassart E. Expression and DNA rearrangement of proto-oncogenes in Cas-Br-E-induced non-T-, non-B-cell leukemias. Leukemia. 1993 Jul;7(7):954–962. [PubMed] [Google Scholar]
  4. Bernard O., Cory S., Gerondakis S., Webb E., Adams J. M. Sequence of the murine and human cellular myc oncogenes and two modes of myc transcription resulting from chromosome translocation in B lymphoid tumours. EMBO J. 1983;2(12):2375–2383. doi: 10.1002/j.1460-2075.1983.tb01749.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bissonnette R. P., Echeverri F., Mahboubi A., Green D. R. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature. 1992 Oct 8;359(6395):552–554. doi: 10.1038/359552a0. [DOI] [PubMed] [Google Scholar]
  6. Blyth K., Terry A., O'Hara M., Baxter E. W., Campbell M., Stewart M., Donehower L. A., Onions D. E., Neil J. C., Cameron E. R. Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. Oncogene. 1995 May 4;10(9):1717–1723. [PubMed] [Google Scholar]
  7. Clark S. S., Chen E., Fizzotti M., Witte O. N., Malkovska V. BCR-ABL and v-abl oncogenes induce distinct patterns of thymic lymphoma involving different lymphocyte subsets. J Virol. 1993 Oct;67(10):6033–6046. doi: 10.1128/jvi.67.10.6033-6046.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  9. Cuypers H. T., Selten G. C., Zijlstra M., de Goede R. E., Melief C. J., Berns A. J. Tumor progression in murine leukemia virus-induced T-cell lymphomas: monitoring clonal selections with viral and cellular probes. J Virol. 1986 Oct;60(1):230–241. doi: 10.1128/jvi.60.1.230-241.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  12. Elson A., Deng C., Campos-Torres J., Donehower L. A., Leder P. The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. Oncogene. 1995 Jul 6;11(1):181–190. [PubMed] [Google Scholar]
  13. Flubacher M. M., Bear S. E., Tsichlis P. N. Replacement of interleukin-2 (IL-2)-generated mitogenic signals by a mink cell focus-forming (MCF) or xenotropic virus-induced IL-9-dependent autocrine loop: implications for MCF virus-induced leukemogenesis. J Virol. 1994 Dec;68(12):7709–7716. doi: 10.1128/jvi.68.12.7709-7716.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haupt Y., Alexander W. S., Barri G., Klinken S. P., Adams J. M. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 1991 May 31;65(5):753–763. doi: 10.1016/0092-8674(91)90383-a. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  17. Howard J. C., Yousefi S., Cheong G., Bernstein A., Ben-David Y. Temporal order and functional analysis of mutations within the Fli-1 and p53 genes during the erythroleukemias induced by F-MuLV. Oncogene. 1993 Oct;8(10):2721–2729. [PubMed] [Google Scholar]
  18. Hsu B., Marin M. C., el-Naggar A. K., Stephens L. C., Brisbay S., McDonnell T. J. Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis. Oncogene. 1995 Jul 6;11(1):175–179. [PubMed] [Google Scholar]
  19. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
  20. Kemp C. J., Donehower L. A., Bradley A., Balmain A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell. 1993 Sep 10;74(5):813–822. doi: 10.1016/0092-8674(93)90461-x. [DOI] [PubMed] [Google Scholar]
  21. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  22. Lazo P. A., Klein-Szanto A. J., Tsichlis P. N. T-cell lymphoma lines derived from rat thymomas induced by Moloney murine leukemia virus: phenotypic diversity and its implications. J Virol. 1990 Aug;64(8):3948–3959. doi: 10.1128/jvi.64.8.3948-3959.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lowe S. W., Jacks T., Housman D. E., Ruley H. E. Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2026–2030. doi: 10.1073/pnas.91.6.2026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Marcu K. B., Banerji J., Penncavage N. A., Lang R., Arnheim N. 5' flanking region of immunoglobulin heavy chain constant region genes displays length heterogeneity in germlines of inbred mouse strains. Cell. 1980 Nov;22(1 Pt 1):187–196. doi: 10.1016/0092-8674(80)90167-1. [DOI] [PubMed] [Google Scholar]
  25. Marin M. C., Hsu B., Meyn R. E., Donehower L. A., el-Naggar A. K., McDonnell T. J. Evidence that p53 and bcl-2 are regulators of a common cell death pathway important for in vivo lymphomagenesis. Oncogene. 1994 Nov;9(11):3107–3112. [PubMed] [Google Scholar]
  26. Mowat M., Cheng A., Kimura N., Bernstein A., Benchimol S. Rearrangements of the cellular p53 gene in erythroleukaemic cells transformed by Friend virus. Nature. 1985 Apr 18;314(6012):633–636. doi: 10.1038/314633a0. [DOI] [PubMed] [Google Scholar]
  27. Munroe D. G., Peacock J. W., Benchimol S. Inactivation of the cellular p53 gene is a common feature of Friend virus-induced erythroleukemia: relationship of inactivation to dominant transforming alleles. Mol Cell Biol. 1990 Jul;10(7):3307–3313. doi: 10.1128/mcb.10.7.3307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Poirier Y., Kozak C., Jolicoeur P. Identification of a common helper provirus integration site in Abelson murine leukemia virus-induced lymphoma DNA. J Virol. 1988 Nov;62(11):3985–3992. doi: 10.1128/jvi.62.11.3985-3992.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Purdie C. A., Harrison D. J., Peter A., Dobbie L., White S., Howie S. E., Salter D. M., Bird C. C., Wyllie A. H., Hooper M. L. Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene. 1994 Feb;9(2):603–609. [PubMed] [Google Scholar]
  31. Rein A. Interference grouping of murine leukemia viruses: a distinct receptor for the MCF-recombinant viruses in mouse cells. Virology. 1982 Jul 15;120(1):251–257. doi: 10.1016/0042-6822(82)90024-1. [DOI] [PubMed] [Google Scholar]
  32. Renauld J. C., Vink A., Louahed J., Van Snick J. Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood. 1995 Mar 1;85(5):1300–1305. [PubMed] [Google Scholar]
  33. 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]
  34. Stewart M., Cameron E., Campbell M., McFarlane R., Toth S., Lang K., Onions D., Neil J. C. Conditional expression and oncogenicity of c-myc linked to a CD2 gene dominant control region. Int J Cancer. 1993 Apr 1;53(6):1023–1030. doi: 10.1002/ijc.2910530628. [DOI] [PubMed] [Google Scholar]
  35. Strasser A., Harris A. W., Bath M. L., Cory S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature. 1990 Nov 22;348(6299):331–333. doi: 10.1038/348331a0. [DOI] [PubMed] [Google Scholar]
  36. Taya Y., Mizusawa S., Nishimura S. Nucleotide sequence of the coding region of the mouse N-myc gene. EMBO J. 1986 Jun;5(6):1215–1219. doi: 10.1002/j.1460-2075.1986.tb04349.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tsukada T., Tomooka Y., Takai S., Ueda Y., Nishikawa S., Yagi T., Tokunaga T., Takeda N., Suda Y., Abe S. Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene. 1993 Dec;8(12):3313–3322. [PubMed] [Google Scholar]
  38. Verbeek S., van Lohuizen M., van der Valk M., Domen J., Kraal G., Berns A. Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally. Mol Cell Biol. 1991 Feb;11(2):1176–1179. doi: 10.1128/mcb.11.2.1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wolf D., Rotter V. Inactivation of p53 gene expression by an insertion of Moloney murine leukemia virus-like DNA sequences. Mol Cell Biol. 1984 Jul;4(7):1402–1410. doi: 10.1128/mcb.4.7.1402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]
  41. van Lohuizen M., Verbeek S., Scheijen B., Wientjens E., van der Gulden H., Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991 May 31;65(5):737–752. doi: 10.1016/0092-8674(91)90382-9. [DOI] [PubMed] [Google Scholar]
  42. van der Putten H., Quint W., van Raaij J., Maandag E. R., Verma I. M., Berns A. M-MuLV-induced leukemogenesis: integration and structure of recombinant proviruses in tumors. Cell. 1981 Jun;24(3):729–739. doi: 10.1016/0092-8674(81)90099-4. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES