Abstract
We introduced a mouse IL-2 cDNA expression vector into an IL-2- dependent mouse helper T cell line HT-2. Transfected cells secreted substantial amounts of IL-2, to which they themselves responded by proliferating without further requirement for exogenous IL-2. The proliferation was a direct function of the cell density and was inhibitable by antibodies against IL-2 or IL-2-R, indicating the autocrine nature of the proliferation. Those producing higher amounts of IL-2 were found to be tumorigenic when inoculated into nude mice. The latency period of tumor development correlated inversely with the level of IL-2 secreted. Tumor cells proliferated in vitro in an IL-2 autocrine fashion indistinguishable from that of the inoculated cells. We thus provide evidence that the aberrant activation of the IL-2 autocrine circuit can lead T cells to malignant transformation.
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- 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]
- Arya S. K., Wong-Staal F., Gallo R. C. T-cell growth factor gene: lack of expression in human T-cell leukemia-lymphoma virus-infected cells. Science. 1984 Mar 9;223(4640):1086–1087. doi: 10.1126/science.6320374. [DOI] [PubMed] [Google Scholar]
- Boshart M., Weber F., Jahn G., Dorsch-Häsler K., Fleckenstein B., Schaffner W. A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell. 1985 Jun;41(2):521–530. doi: 10.1016/s0092-8674(85)80025-8. [DOI] [PubMed] [Google Scholar]
- Cann A. J., Rosenblatt J. D., Wachsman W., Shah N. P., Chen I. S. Identification of the gene responsible for human T-cell leukaemia virus transcriptional regulation. Nature. 1985 Dec 12;318(6046):571–574. doi: 10.1038/318571a0. [DOI] [PubMed] [Google Scholar]
- Cross S. L., Feinberg M. B., Wolf J. B., Holbrook N. J., Wong-Staal F., Leonard W. J. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. doi: 10.1016/0092-8674(87)90754-9. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- Dvoretzky I., Shober R., Chattopadhyay S. K., Lowy D. R. A quantitative in vitro focus assay for bovine papilloma virus. Virology. 1980 Jun;103(2):369–375. doi: 10.1016/0042-6822(80)90195-6. [DOI] [PubMed] [Google Scholar]
- Felber B. K., Paskalis H., Kleinman-Ewing C., Wong-Staal F., Pavlakis G. N. The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science. 1985 Aug 16;229(4714):675–679. doi: 10.1126/science.2992082. [DOI] [PubMed] [Google Scholar]
- Fujisawa J., Seiki M., Kiyokawa T., Yoshida M. Functional activation of the long terminal repeat of human T-cell leukemia virus type I by a trans-acting factor. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2277–2281. doi: 10.1073/pnas.82.8.2277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- Jaye M., Lyall R. M., Mudd R., Schlessinger J., Sarver N. Expression of acidic fibroblast growth factor cDNA confers growth advantage and tumorigenesis to Swiss 3T3 cells. EMBO J. 1988 Apr;7(4):963–969. doi: 10.1002/j.1460-2075.1988.tb02902.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
- Laker C., Stocking C., Bergholz U., Hess N., De Lamarter J. F., Ostertag W. Autocrine stimulation after transfer of the granulocyte/macrophage colony-stimulating factor gene and autonomous growth are distinct but interdependent steps in the oncogenic pathway. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8458–8462. doi: 10.1073/pnas.84.23.8458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Maeda M., Arima N., Daitoku Y., Kashihara M., Okamoto H., Uchiyama T., Shirono K., Matsuoka M., Hattori T., Takatsuki K. Evidence for the interleukin-2 dependent expansion of leukemic cells in adult T cell leukemia. Blood. 1987 Nov;70(5):1407–1411. [PubMed] [Google Scholar]
- 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]
- 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]
- Ochi A., Hawley R. G., Shulman M. J., Hozumi N. Transfer of a cloned immunoglobulin light-chain gene to mutant hybridoma cells restores specific antibody production. Nature. 1983 Mar 24;302(5906):340–342. doi: 10.1038/302340a0. [DOI] [PubMed] [Google Scholar]
- Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
- Ortega G., Robb R. J., Shevach E. M., Malek T. R. The murine IL 2 receptor. I. Monoclonal antibodies that define distinct functional epitopes on activated T cells and react with activated B cells. J Immunol. 1984 Oct;133(4):1970–1975. [PubMed] [Google Scholar]
- 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]
- 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]
- Schaffner W. Direct transfer of cloned genes from bacteria to mammalian cells. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2163–2167. doi: 10.1073/pnas.77.4.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seiki M., Hattori S., Hirayama Y., Yoshida M. Human adult T-cell leukemia virus: complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3618–3622. doi: 10.1073/pnas.80.12.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith K. A., Favata M. F., Oroszlan S. Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol. 1983 Oct;131(4):1808–1815. [PubMed] [Google Scholar]
- Smith K. A. T-cell growth factor and glucocorticoids: opposing regulatory hormones in neoplastic T-cell growth. Immunobiology. 1982 Mar;161(1-2):157–173. doi: 10.1016/S0171-2985(82)80023-5. [DOI] [PubMed] [Google Scholar]
- Sodroski J., Rosen C., Goh W. C., Haseltine W. A transcriptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science. 1985 Jun 21;228(4706):1430–1434. doi: 10.1126/science.2990028. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- 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]
- Tsudo M., Uchiyama T., Uchino H., Yodoi J. Failure of regulation of Tac antigen/TCGF receptor on adult T-cell leukemia cells by anti-Tac monoclonal antibody. Blood. 1983 May;61(5):1014–1016. [PubMed] [Google Scholar]
- 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]
- 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]
- Watson J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med. 1979 Dec 1;150(6):1510–1519. doi: 10.1084/jem.150.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamada G., Kitamura Y., Sonoda H., Harada H., Taki S., Mulligan R. C., Osawa H., Diamantstein T., Yokoyama S., Taniguchi T. Retroviral expression of the human IL-2 gene in a murine T cell line results in cell growth autonomy and tumorigenicity. EMBO J. 1987 Sep;6(9):2705–2709. doi: 10.1002/j.1460-2075.1987.tb02563.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]