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. 1991 Mar;11(3):1590–1597. doi: 10.1128/mcb.11.3.1590

Interleukin-7 retroviruses transform pre-B cells by an autocrine mechanism not evident in Abelson murine.

R W Overell 1, L Clark 1, D Lynch 1, R Jerzy 1, A Schmierer 1, K E Weisser 1, A E Namen 1, R G Goodwin 1
PMCID: PMC369450  PMID: 1996110

Abstract

In this study, we have constructed retroviral vectors expressing the interleukin-7 (IL-7) cDNA and have used infection with these retroviruses to express this cytokine endogenously in an IL-7-dependent pre-B-cell line. Infection with IL-7 retroviruses, but not with a control retrovirus, resulted in the conversion of the cells to IL-7 independence. The frequency at which this occurred, together with data on vector expression levels, indicated that secondary events were required for factor independence in this system. Southern analysis showed that the IL-7-dependent clones harbored unrearranged copies of the vector proviruses. The factor-independent cells produced variable quantities of IL-7 as measured by an IL-7-specific bioassay, and their proliferation could be substantially inhibited by a neutralizing antibody directed against IL-7, indicating that a classical autocrine-mechanism was responsible for their transformation. These IL-7-independent cells were tumorigenic, in contrast to the parental IL-7-dependent cells or those infected with a control vector. These results showed that IL-7 could participate in the malignant transformation of pre-B cells. However, neither of two Abelson murine leukemia virus (A-MuLV)-transformed pre-B-cell lines expressed detectable IL-7 mRNA, at a level of sensitivity corresponding to less than one molecule of mRNA per cell. Moreover, the proliferation of the A-MuLV transformants was unaffected by addition of the IL-7 antisera under conditions in which parallel experiments with IL-7 virus-infected cells resulted in greater than 70% growth inhibition. Thus, transformation of pre-B cells by A-MuLV was not associated with a demonstrable autocrine loop of IL-7 synthesis. These results show that IL-7 can participate in the malignant transformation of pre-B cells and suggest studies aimed at assessing the role of autocrine production of IL-7 in the generation of human leukemias and lymphomas.

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Selected References

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

  1. Adams J. M., Harris A. W., Pinkert C. A., Corcoran L. M., Alexander W. S., Cory S., Palmiter R. D., Brinster R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985 Dec 12;318(6046):533–538. doi: 10.1038/318533a0. [DOI] [PubMed] [Google Scholar]
  2. Adkins B., Leutz A., Graf T. Autocrine growth induced by src-related oncogenes in transformed chicken myeloid cells. Cell. 1984 Dec;39(3 Pt 2):439–445. doi: 10.1016/0092-8674(84)90451-3. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Baltimore D., Rosenberg N., Witte O. N. Transformation of immature lymphoid cells by Abelson murine leukemia virus. Immunol Rev. 1979;48:3–22. doi: 10.1111/j.1600-065x.1979.tb00296.x. [DOI] [PubMed] [Google Scholar]
  5. Baumbach W. R., Stanley E. R., Cole M. D. Induction of clonal monocyte-macrophage tumors in vivo by a mouse c-myc retrovirus: rearrangement of the CSF-1 gene as a secondary transforming event. Mol Cell Biol. 1987 Feb;7(2):664–671. doi: 10.1128/mcb.7.2.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bender M. A., Palmer T. D., Gelinas R. E., Miller A. D. Evidence that the packaging signal of Moloney murine leukemia virus extends into the gag region. J Virol. 1987 May;61(5):1639–1646. doi: 10.1128/jvi.61.5.1639-1646.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chang J. M., Metcalf D., Lang R. A., Gonda T. J., Johnson G. R. Nonneoplastic hematopoietic myeloproliferative syndrome induced by dysregulated multi-CSF (IL-3) expression. Blood. 1989 May 1;73(6):1487–1497. [PubMed] [Google Scholar]
  8. Cheng G. Y., Kelleher C. A., Miyauchi J., Wang C., Wong G., Clark S. C., McCulloch E. A., Minden M. D. Structure and expression of genes of GM-CSF and G-CSF in blast cells from patients with acute myeloblastic leukemia. Blood. 1988 Jan;71(1):204–208. [PubMed] [Google Scholar]
  9. Coffman R. L., Weissman I. L. B220: a B cell-specific member of th T200 glycoprotein family. Nature. 1981 Feb 19;289(5799):681–683. doi: 10.1038/289681a0. [DOI] [PubMed] [Google Scholar]
  10. Cook W. D., Metcalf D., Nicola N. A., Burgess A. W., Walker F. Malignant transformation of a growth factor-dependent myeloid cell line by Abelson virus without evidence of an autocrine mechanism. Cell. 1985 Jul;41(3):677–683. doi: 10.1016/s0092-8674(85)80048-9. [DOI] [PubMed] [Google Scholar]
  11. Cook W. D. Thymocyte subsets transformed by Abelson murine leukemia virus. Mol Cell Biol. 1985 Feb;5(2):390–397. doi: 10.1128/mcb.5.2.390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Durand D. B., Kamoun M., Norris C. A., Holbrook N. J., Greengard J. S., Crabtree G. R., Kant J. A. Retroviral activation of interleukin 2 gene in a gibbon ape T cell lymphoma line. J Exp Med. 1986 Nov 1;164(5):1723–1734. doi: 10.1084/jem.164.5.1723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Goodwin R. G., Friend D., Ziegler S. F., Jerzy R., Falk B. A., Gimpel S., Cosman D., Dower S. K., March C. J., Namen A. E. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell. 1990 Mar 23;60(6):941–951. doi: 10.1016/0092-8674(90)90342-c. [DOI] [PubMed] [Google Scholar]
  15. Humphries R. K., Abraham S., Krystal G., Lansdorp P., Lemoine F., Eaves C. J. Activation of multiple hemopoietic growth factor genes in Abelson virus-transformed myeloid cells. Exp Hematol. 1988 Oct;16(9):774–781. [PubMed] [Google Scholar]
  16. Idzerda R. L., March C. J., Mosley B., Lyman S. D., Vanden Bos T., Gimpel S. D., Din W. S., Grabstein K. H., Widmer M. B., Park L. S. Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J Exp Med. 1990 Mar 1;171(3):861–873. doi: 10.1084/jem.171.3.861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Johnson G. R., Gonda T. J., Metcalf D., Hariharan I. K., Cory S. A lethal myeloproliferative syndrome in mice transplanted with bone marrow cells infected with a retrovirus expressing granulocyte-macrophage colony stimulating factor. EMBO J. 1989 Feb;8(2):441–448. doi: 10.1002/j.1460-2075.1989.tb03396.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kamps M. P., Murre C., Sun X. H., Baltimore D. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell. 1990 Feb 23;60(4):547–555. doi: 10.1016/0092-8674(90)90658-2. [DOI] [PubMed] [Google Scholar]
  19. Kawano M., Hirano T., Matsuda T., Taga T., Horii Y., Iwato K., Asaoku H., Tang B., Tanabe O., Tanaka H. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988 Mar 3;332(6159):83–85. doi: 10.1038/332083a0. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. 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]
  23. Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989 May 4;339(6219):27–30. doi: 10.1038/339027a0. [DOI] [PubMed] [Google Scholar]
  24. Morrissey P. J., Goodwin R. G., Nordan R. P., Anderson D., Grabstein K. H., Cosman D., Sims J., Lupton S., Acres B., Reed S. G. Recombinant interleukin 7, pre-B cell growth factor, has costimulatory activity on purified mature T cells. J Exp Med. 1989 Mar 1;169(3):707–716. doi: 10.1084/jem.169.3.707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
  26. Namen A. E., Schmierer A. E., March C. J., Overell R. W., Park L. S., Urdal D. L., Mochizuki D. Y. B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors. J Exp Med. 1988 Mar 1;167(3):988–1002. doi: 10.1084/jem.167.3.988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nourse J., Mellentin J. D., Galili N., Wilkinson J., Stanbridge E., Smith S. D., Cleary M. L. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell. 1990 Feb 23;60(4):535–545. doi: 10.1016/0092-8674(90)90657-z. [DOI] [PubMed] [Google Scholar]
  28. Overell R. W., Watson J. D., Gallis B., Weisser K. E., Cosman D., Widmer M. B. Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src. Mol Cell Biol. 1987 Oct;7(10):3394–3401. doi: 10.1128/mcb.7.10.3394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Overell R. W., Weisser K. E., Hess B., Namen A. E., Grabstein K. H. Stage-specific transformation of murine B lineage cells by ras and myc. Oncogene. 1989 Dec;4(12):1425–1432. [PubMed] [Google Scholar]
  30. Park L. S., Friend D. J., Schmierer A. E., Dower S. K., Namen A. E. Murine interleukin 7 (IL-7) receptor. Characterization on an IL-7-dependent cell line. J Exp Med. 1990 Apr 1;171(4):1073–1089. doi: 10.1084/jem.171.4.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pierce J. H., Di Fiore P. P., Aaronson S. A., Potter M., Pumphrey J., Scott A., Ihle J. N. Neoplastic transformation of mast cells by Abelson-MuLV: abrogation of IL-3 dependence by a nonautocrine mechanism. Cell. 1985 Jul;41(3):685–693. doi: 10.1016/s0092-8674(85)80049-0. [DOI] [PubMed] [Google Scholar]
  32. Rosenberg N., Baltimore D. A quantitative assay for transformation of bone marrow cells by Abelson murine leukemia virus. J Exp Med. 1976 Jun 1;143(6):1453–1463. doi: 10.1084/jem.143.6.1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Schwartz R. C., Stanton L. W., Riley S. C., Marcu K. B., Witte O. N. Synergism of v-myc and v-Ha-ras in the in vitro neoplastic progression of murine lymphoid cells. Mol Cell Biol. 1986 Sep;6(9):3221–3231. doi: 10.1128/mcb.6.9.3221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Southern P. J., Berg P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J Mol Appl Genet. 1982;1(4):327–341. [PubMed] [Google Scholar]
  35. 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]
  36. Sutherland G. R., Baker E., Fernandez K. E., Callen D. F., Goodwin R. G., Lupton S., Namen A. E., Shannon M. F., Vadas M. A. The gene for human interleukin 7 (IL7) is at 8q12-13. Hum Genet. 1989 Jul;82(4):371–372. doi: 10.1007/BF00274000. [DOI] [PubMed] [Google Scholar]
  37. Tohyama N., Karasuyama H., Tada T. Growth autonomy and tumorigenicity of interleukin 6-dependent B cells transfected with interleukin 6 cDNA. J Exp Med. 1990 Feb 1;171(2):389–400. doi: 10.1084/jem.171.2.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Whitlock C. A., Witte O. N. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3608–3612. doi: 10.1073/pnas.79.11.3608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Williams D. E., Namen A. E., Mochizuki D. Y., Overell R. W. Clonal growth of murine pre-B colony-forming cells and their targeted infection by a retroviral vector: dependence on interleukin-7. Blood. 1990 Mar 1;75(5):1132–1138. [PubMed] [Google Scholar]
  40. Williams G. T. High-efficiency preparation of DNA from limiting quantities of eukaryotic cells for hybridization analysis. Gene. 1987;53(1):121–126. doi: 10.1016/0378-1119(87)90099-0. [DOI] [PubMed] [Google Scholar]
  41. Wong P. M., Chung S. W., Nienhuis A. W. Retroviral transfer and expression of the interleukin-3 gene in hemopoietic cells. Genes Dev. 1987 Jun;1(4):358–365. doi: 10.1101/gad.1.4.358. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Young D. C., Griffin J. D. Autocrine secretion of GM-CSF in acute myeloblastic leukemia. Blood. 1986 Nov;68(5):1178–1181. [PubMed] [Google Scholar]
  44. Yunis J. J. The chromosomal basis of human neoplasia. Science. 1983 Jul 15;221(4607):227–236. doi: 10.1126/science.6336310. [DOI] [PubMed] [Google Scholar]
  45. 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]

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