Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1989 Jan;9(1):67–73. doi: 10.1128/mcb.9.1.67

Oncogene cooperation in lymphocyte transformation: malignant conversion of E mu-myc transgenic pre-B cells in vitro is enhanced by v-H-ras or v-raf but not v-abl.

W S Alexander 1, J M Adams 1, S Cory 1
PMCID: PMC362146  PMID: 2784537

Abstract

Although transgenic mice bearing a c-myc gene controlled by the immunoglobulin heavy-chain enhancer (E mu) eventually develop B-lymphoid tumors, B-lineage cells from preneoplastic bone marrow express the transgene but do not grow autonomously or produce tumors in mice. To determine whether other oncogenes can cooperate with myc to transform B-lineage cells, we compared the in vitro growth and tumorigenicity of normal and E mu-myc bone marrow cells infected with retroviruses bearing the v-H-ras, v-raf, or v-abl oncogene. The v-H-ras and v-raf viruses both generated a rapid polyclonal expansion of E mu-myc pre-B bone marrow cells in liquid culture and 10- to 100-fold more pre-B lymphoid colonies than normal in soft agar. The infected transgenic cells were autonomous, cloned efficiently in agar, and grew as tumors in nude mice. While many pre-B cells from normal marrow could also be induced to proliferate by the v-raf virus, these cells required a stromal feeder layer, did not clone in agar, and were not malignant. Most normal cells stimulated to grow by v-H-ras also cloned poorly in agar, and only rare cells were tumorigenic. With the v-abl virus, no more cells were transformed from E mu-myc than normal marrow and the proportion of tumorigenic pre-B clones was not elevated. These results suggest that both v-H-ras and v-raf, but apparently not v-abl, collaborate with constitutive myc expression to promote autonomous proliferation and tumorigenicity of pre-B lymphoid cells.

Full text

PDF
67

Images in this article

69Image
on p.69
71Image
on p.71

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. Alexander W. S., Schrader J. W., Adams J. M. Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice. Mol Cell Biol. 1987 Apr;7(4):1436–1444. doi: 10.1128/mcb.7.4.1436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cerni C., Mougneau E., Cuzin F. Transfer of 'immortalizing' oncogenes into rat fibroblasts induces both high rates of sister chromatid exchange and appearance of abnormal karyotypes. Exp Cell Res. 1987 Feb;168(2):439–446. doi: 10.1016/0014-4827(87)90016-4. [DOI] [PubMed] [Google Scholar]
  4. Cleveland J. L., Jansen H. W., Bister K., Fredrickson T. N., Morse H. C., 3rd, Ihle J. N., Rapp U. R. Interaction between Raf and Myc oncogenes in transformation in vivo and in vitro. J Cell Biochem. 1986;30(3):195–218. doi: 10.1002/jcb.240300303. [DOI] [PubMed] [Google Scholar]
  5. Cory S. Activation of cellular oncogenes in hemopoietic cells by chromosome translocation. Adv Cancer Res. 1986;47:189–234. doi: 10.1016/s0065-230x(08)60200-6. [DOI] [PubMed] [Google Scholar]
  6. Diamond L. E., Guerrero I., Pellicer A. Concomitant K- and N-ras gene point mutations in clonal murine lymphoma. Mol Cell Biol. 1988 May;8(5):2233–2236. doi: 10.1128/mcb.8.5.2233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dyall-Smith D., Cory S. Transformation of bone marrow cells from E mu-myc transgenic mice by Abelson murine leukemia virus and Harvey murine sarcoma virus. Oncogene Res. 1988 May;2(4):403–409. [PubMed] [Google Scholar]
  8. 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]
  9. Harris A. W., Pinkert C. A., Crawford M., Langdon W. Y., Brinster R. L., Adams J. M. The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med. 1988 Feb 1;167(2):353–371. doi: 10.1084/jem.167.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Holmes K. L., Pierce J. H., Davidson W. F., Morse H. C., 3rd Murine hematopoietic cells with pre-B or pre-B/myeloid characteristics are generated by in vitro transformation with retroviruses containing fes, ras, abl, and src oncogenes. J Exp Med. 1986 Aug 1;164(2):443–457. doi: 10.1084/jem.164.2.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Langdon W. Y., Harris A. W., Cory S., Adams J. M. The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell. 1986 Oct 10;47(1):11–18. doi: 10.1016/0092-8674(86)90361-2. [DOI] [PubMed] [Google Scholar]
  13. Leder A., Pattengale P. K., Kuo A., Stewart T. A., Leder P. Consequences of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasms and normal development. Cell. 1986 May 23;45(4):485–495. doi: 10.1016/0092-8674(86)90280-1. [DOI] [PubMed] [Google Scholar]
  14. Leder P., Battey J., Lenoir G., Moulding C., Murphy W., Potter H., Stewart T., Taub R. Translocations among antibody genes in human cancer. Science. 1983 Nov 18;222(4625):765–771. doi: 10.1126/science.6356357. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Murray M. J., Cunningham J. M., Parada L. F., Dautry F., Lebowitz P., Weinberg R. A. The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. Cell. 1983 Jul;33(3):749–757. doi: 10.1016/0092-8674(83)90017-x. [DOI] [PubMed] [Google Scholar]
  17. Ohno S., Migita S., Wiener F., Babonits M., Klein G., Mushinski J. F., Potter M. Chromosomal translocations activating myc sequences and transduction of v-abl are critical events in the rapid induction of plasmacytomas by pristane and abelson virus. J Exp Med. 1984 Jun 1;159(6):1762–1777. doi: 10.1084/jem.159.6.1762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pierce J. H., Aaronson S. A. BALB- and Harvey-murine sarcoma virus transformation of a novel lymphoid progenitor cell. J Exp Med. 1982 Sep 1;156(3):873–887. doi: 10.1084/jem.156.3.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Potter M., Sklar M. D., Rowe W. P. Rapid viral induction of plasmacytomas in pristane-primed BALB-c mice. Science. 1973 Nov 9;182(4112):592–594. doi: 10.1126/science.182.4112.592. [DOI] [PubMed] [Google Scholar]
  20. Rapp U. R., Cleveland J. L., Fredrickson T. N., Holmes K. L., Morse H. C., 3rd, Jansen H. W., Patschinsky T., Bister K. Rapid induction of hemopoietic neoplasms in newborn mice by a raf(mil)/myc recombinant murine retrovirus. J Virol. 1985 Jul;55(1):23–33. doi: 10.1128/jvi.55.1.23-33.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rapp U. R., Goldsborough M. D., Mark G. E., Bonner T. I., Groffen J., Reynolds F. H., Jr, Stephenson J. R. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4218–4222. doi: 10.1073/pnas.80.14.4218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ridley A. J., Paterson H. F., Noble M., Land H. Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J. 1988 Jun;7(6):1635–1645. doi: 10.1002/j.1460-2075.1988.tb02990.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rosenberg N. Abelson leukemia virus. Curr Top Microbiol Immunol. 1982;101:95–126. doi: 10.1007/978-3-642-68654-2_5. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Sinn E., Muller W., Pattengale P., Tepler I., Wallace R., Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987 May 22;49(4):465–475. doi: 10.1016/0092-8674(87)90449-1. [DOI] [PubMed] [Google Scholar]
  26. Suda Y., Aizawa S., Hirai S., Inoue T., Furuta Y., Suzuki M., Hirohashi S., Ikawa Y. Driven by the same Ig enhancer and SV40 T promoter ras induced lung adenomatous tumors, myc induced pre-B cell lymphomas and SV40 large T gene a variety of tumors in transgenic mice. EMBO J. 1987 Dec 20;6(13):4055–4065. doi: 10.1002/j.1460-2075.1987.tb02751.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Vogt M., Lesley J., Bogenberger J., Volkman S., Haas M. Coinfection with viruses carrying the v-Ha-ras and v-myc oncogenes leads to growth factor independence by an indirect mechanism. Mol Cell Biol. 1986 Oct;6(10):3545–3549. doi: 10.1128/mcb.6.10.3545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Whitlock C. A., Robertson D., Witte O. N. Murine B cell lymphopoiesis in long term culture. J Immunol Methods. 1984 Mar 16;67(2):353–369. doi: 10.1016/0022-1759(84)90475-7. [DOI] [PubMed] [Google Scholar]
  29. Whitlock C. A., Tidmarsh G. F., Muller-Sieburg C., Weissman I. L. Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell. 1987 Mar 27;48(6):1009–1021. doi: 10.1016/0092-8674(87)90709-4. [DOI] [PubMed] [Google Scholar]
  30. Whitlock C. A., Witte O. N. Abelson virus-infected cells can exhibit restricted in vitro growth and low oncogenic potential. J Virol. 1981 Nov;40(2):577–584. doi: 10.1128/jvi.40.2.577-584.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Whitlock C. A., Witte O. N. The complexity of virus--cell interactions in Abelson virus infection of lymphoid and other hematopoietic cells. Adv Immunol. 1985;37:73–98. doi: 10.1016/s0065-2776(08)60338-7. [DOI] [PubMed] [Google Scholar]
  32. Whitlock C. A., Ziegler S. F., Witte O. N. Progression of the transformed phenotype in clonal lines of Abelson virus-infected lymphocytes. Mol Cell Biol. 1983 Apr;3(4):596–604. doi: 10.1128/mcb.3.4.596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ziegler S. F., Whitlock C. A., Goff S. P., Gifford A., Witte O. N. Lethal effect of the Abelson murine leukemia virus transforming gene product. Cell. 1981 Dec;27(3 Pt 2):477–486. doi: 10.1016/0092-8674(81)90389-5. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES