Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1987 Sep;6(9):2705–2709. doi: 10.1002/j.1460-2075.1987.tb02563.x

Retroviral expression of the human IL-2 gene in a murine T cell line results in cell growth autonomy and tumorigenicity.

G Yamada 1, Y Kitamura 1, H Sonoda 1, H Harada 1, S Taki 1, R C Mulligan 1, H Osawa 1, T Diamantstein 1, S Yokoyama 1, T Taniguchi 1
PMCID: PMC553693  PMID: 3119325

Abstract

In mature T lymphocytes (T cells) the regulated expression of the genes for interleukin-2 (IL-2) and its receptor (IL-2R) constitutes an essential part in controlling the cell growth. Evidence has been provided which suggests the involvement of an aberrant function of the IL-2 system in developing T cell neoplasms, particularly the adult T cell leukemia/lymphoma (ATL). As an approach to examine the extent of the IL-2 system contribution to T cell neoplasms, we created the experimental conditions wherein both IL-2 and IL-2R are expressed constitutively in a murine T cell line. We made use of a retroviral vector to infect an IL-2-dependent CTLL-2 line and lead to the expression of human IL-2. Here, we show that the virus-infected cells not only proliferate in vitro in the absence of exogenously supplied IL-2 under certain conditions, but also develop tumors (lymphomas) in nude and syngeneic mice.

Full text

PDF
2705

Images in this article

Selected References

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

  1. Arima N., Daitoku Y., Ohgaki S., Fukumori J., Tanaka H., Yamamoto Y., Fujimoto K., Onoue K. Autocrine growth of interleukin 2-producing leukemic cells in a patient with adult T cell leukemia. Blood. 1986 Sep;68(3):779–782. [PubMed] [Google Scholar]
  2. Cepko C. L., Roberts B. E., Mulligan R. C. Construction and applications of a highly transmissible murine retrovirus shuttle vector. Cell. 1984 Jul;37(3):1053–1062. doi: 10.1016/0092-8674(84)90440-9. [DOI] [PubMed] [Google Scholar]
  3. Depper J. M., Leonard W. J., Krönke M., Waldmann T. A., Greene W. C. Augmented T cell growth factor receptor expression in HTLV-1-infected human leukemic T cells. J Immunol. 1984 Oct;133(4):1691–1695. [PubMed] [Google Scholar]
  4. Doolittle R. F., Hunkapiller M. W., Hood L. E., Devare S. G., Robbins K. C., Aaronson S. A., Antoniades H. N. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983 Jul 15;221(4607):275–277. doi: 10.1126/science.6304883. [DOI] [PubMed] [Google Scholar]
  5. Duprez V., Lenoir G., Dautry-Varsat A. Autocrine growth stimulation of a human T-cell lymphoma line by interleukin 2. Proc Natl Acad Sci U S A. 1985 Oct;82(20):6932–6936. doi: 10.1073/pnas.82.20.6932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Durand D. B., Bush M. R., Morgan J. G., Weiss A., Crabtree G. R. A 275 basepair fragment at the 5' end of the interleukin 2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor. J Exp Med. 1987 Feb 1;165(2):395–407. doi: 10.1084/jem.165.2.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fujita T., Shibuya H., Ohashi T., Yamanishi K., Taniguchi T. Regulation of human interleukin-2 gene: functional DNA sequences in the 5' flanking region for the gene expression in activated T lymphocytes. Cell. 1986 Aug 1;46(3):401–405. doi: 10.1016/0092-8674(86)90660-4. [DOI] [PubMed] [Google Scholar]
  8. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  9. Gillis S., Smith K. A. Long term culture of tumour-specific cytotoxic T cells. Nature. 1977 Jul 14;268(5616):154–156. doi: 10.1038/268154a0. [DOI] [PubMed] [Google Scholar]
  10. Gootenberg J. E., Ruscetti F. W., Mier J. W., Gazdar A., Gallo R. C. Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor. J Exp Med. 1981 Nov 1;154(5):1403–1418. doi: 10.1084/jem.154.5.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graf T., von Weizsaecker F., Grieser S., Coll J., Stehelin D., Patschinsky T., Bister K., Bechade C., Calothy G., Leutz A. v-mil induces autocrine growth and enhanced tumorigenicity in v-myc-transformed avian macrophages. Cell. 1986 May 9;45(3):357–364. doi: 10.1016/0092-8674(86)90321-1. [DOI] [PubMed] [Google Scholar]
  12. Greene W. C., Leonard W. J. The human interleukin-2 receptor. Annu Rev Immunol. 1986;4:69–95. doi: 10.1146/annurev.iy.04.040186.000441. [DOI] [PubMed] [Google Scholar]
  13. Greene W. C., Leonard W. J., Wano Y., Svetlik P. B., Peffer N. J., Sodroski J. G., Rosen C. A., Goh W. C., Haseltine W. A. Trans-activator gene of HTLV-II induces IL-2 receptor and IL-2 cellular gene expression. Science. 1986 May 16;232(4752):877–880. doi: 10.1126/science.3010456. [DOI] [PubMed] [Google Scholar]
  14. Hattori T., Uchiyama T., Toibana T., Takatsuki K., Uchino H. Surface phenotype of Japanese adult T-cell leukemia cells characterized by monoclonal antibodies. Blood. 1981 Sep;58(3):645–647. [PubMed] [Google Scholar]
  15. Inoue J., Seiki M., Taniguchi T., Tsuru S., Yoshida M. Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 1986 Nov;5(11):2883–2888. doi: 10.1002/j.1460-2075.1986.tb04583.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kaplan P. L., Anderson M., Ozanne B. Transforming growth factor(s) production enables cells to grow in the absence of serum: an autocrine system. Proc Natl Acad Sci U S A. 1982 Jan;79(2):485–489. doi: 10.1073/pnas.79.2.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lang R. A., Metcalf D., Gough N. M., Dunn A. R., Gonda T. J. Expression of a hemopoietic growth factor cDNA in a factor-dependent cell line results in autonomous growth and tumorigenicity. Cell. 1985 Dec;43(2 Pt 1):531–542. doi: 10.1016/0092-8674(85)90182-5. [DOI] [PubMed] [Google Scholar]
  18. Maeda M., Shimizu A., Ikuta K., Okamoto H., Kashihara M., Uchiyama T., Honjo T., Yodoi J. Origin of human T-lymphotrophic virus I-positive T cell lines in adult T cell leukemia. Analysis of T cell receptor gene rearrangement. J Exp Med. 1985 Dec 1;162(6):2169–2174. doi: 10.1084/jem.162.6.2169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  20. Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
  21. Osawa H., Diamantstein T. A rat monoclonal antibody that binds specifically to mouse T lymphoblasts and inhibits IL 2 receptor functions: a putative anti-IL 2 receptor antibody. J Immunol. 1984 May;132(5):2445–2450. [PubMed] [Google Scholar]
  22. Rosenthal A., Lindquist P. B., Bringman T. S., Goeddel D. V., Derynck R. Expression in rat fibroblasts of a human transforming growth factor-alpha cDNA results in transformation. Cell. 1986 Jul 18;46(2):301–309. doi: 10.1016/0092-8674(86)90747-6. [DOI] [PubMed] [Google Scholar]
  23. Smith K. A. T-cell growth factor. Immunol Rev. 1980;51:337–357. doi: 10.1111/j.1600-065x.1980.tb00327.x. [DOI] [PubMed] [Google Scholar]
  24. Sporn M. B., Roberts A. B. Autocrine growth factors and cancer. 1985 Feb 28-Mar 6Nature. 313(6005):745–747. doi: 10.1038/313745a0. [DOI] [PubMed] [Google Scholar]
  25. Sporn M. B., Todaro G. J. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980 Oct 9;303(15):878–880. doi: 10.1056/NEJM198010093031511. [DOI] [PubMed] [Google Scholar]
  26. Stern D. F., Hare D. L., Cecchini M. A., Weinberg R. A. Construction of a novel oncogene based on synthetic sequences encoding epidermal growth factor. Science. 1987 Jan 16;235(4786):321–324. doi: 10.1126/science.3492043. [DOI] [PubMed] [Google Scholar]
  27. Taniguchi T., Matsui H., Fujita T., Hatakeyama M., Kashima N., Fuse A., Hamuro J., Nishi-Takaoka C., Yamada G. Molecular analysis of the interleukin-2 system. Immunol Rev. 1986 Aug;92:121–133. doi: 10.1111/j.1600-065x.1986.tb01497.x. [DOI] [PubMed] [Google Scholar]
  28. Taniguchi T., Matsui H., Fujita T., Takaoka C., Kashima N., Yoshimoto R., Hamuro J. Structure and expression of a cloned cDNA for human interleukin-2. Nature. 1983 Mar 24;302(5906):305–310. doi: 10.1038/302305a0. [DOI] [PubMed] [Google Scholar]
  29. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Todaro G. J., De Larco J. E., Nissley S. P., Rechler M. M. MSA and EGF receptors on sarcoma virus transformed cells and human fibrosarcoma cells in culture. Nature. 1977 Jun 9;267(5611):526–528. doi: 10.1038/267526a0. [DOI] [PubMed] [Google Scholar]
  31. Uchiyama T., Hori T., Tsudo M., Wano Y., Umadome H., Tamori S., Yodoi J., Maeda M., Sawami H., Uchino H. Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. J Clin Invest. 1985 Aug;76(2):446–453. doi: 10.1172/JCI111992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Waldmann T. A., Greene W. C., Sarin P. S., Saxinger C., Blayney D. W., Blattner W. A., Goldman C. K., Bongiovanni K., Sharrow S., Depper J. M. Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor. J Clin Invest. 1984 Jun;73(6):1711–1718. doi: 10.1172/JCI111379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Watanabe S., Lazar E., Sporn M. B. Transformation of normal rat kidney (NRK) cells by an infectious retrovirus carrying a synthetic rat type alpha transforming growth factor gene. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1258–1262. doi: 10.1073/pnas.84.5.1258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Waterfield M. D., Scrace G. T., Whittle N., Stroobant P., Johnsson A., Wasteson A., Westermark B., Heldin C. H., Huang J. S., Deuel T. F. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature. 1983 Jul 7;304(5921):35–39. doi: 10.1038/304035a0. [DOI] [PubMed] [Google Scholar]
  35. Wigler M., Sweet R., Sim G. K., Wold B., Pellicer A., Lacy E., Maniatis T., Silverstein S., Axel R. Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell. 1979 Apr;16(4):777–785. doi: 10.1016/0092-8674(79)90093-x. [DOI] [PubMed] [Google Scholar]
  36. de Larco J. E., Todaro G. J. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978 Aug;75(8):4001–4005. doi: 10.1073/pnas.75.8.4001. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES