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. 1997 Jun 2;16(11):2985–2995. doi: 10.1093/emboj/16.11.2985

Targeted expression of MYCN causes neuroblastoma in transgenic mice.

W A Weiss 1, K Aldape 1, G Mohapatra 1, B G Feuerstein 1, J M Bishop 1
PMCID: PMC1169917  PMID: 9214616

Abstract

The proto-oncogene MYCN is often amplified in human neuroblastomas. The assumption that the amplification contributes to tumorigenesis has never been tested directly. We have created transgenic mice that overexpress MYCN in neuroectodermal cells and develop neuroblastoma. Analysis of tumors by comparative genomic hybridization revealed gains and losses of at least seven chromosomal regions, all of which are syntenic with comparable abnormalities detected in human neuroblastomas. In addition, we have shown that increases in MYCN dosage or deficiencies in either of the tumor suppressor genes NF1 or RB1 can augment tumorigenesis by the transgene. Our results provide direct evidence that MYCN can contribute to the genesis of neuroblastoma, suggest that the genetic events involved in the genesis of neuroblastoma can be tumorigenic in more than one chronological sequence, and offer a model for further study of the pathogenesis and therapy of neuroblastoma.

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Selected References

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  1. Aguzzi A., Wagner E. F., Williams R. L., Courtneidge S. A. Sympathetic hyperplasia and neuroblastomas in transgenic mice expressing polyoma middle T antigen. New Biol. 1990 Jun;2(6):533–543. [PubMed] [Google Scholar]
  2. Brodeur G. M., Seeger R. C., Schwab M., Varmus H. E., Bishop J. M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984 Jun 8;224(4653):1121–1124. doi: 10.1126/science.6719137. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Fong C. T., White P. S., Peterson K., Sapienza C., Cavenee W. K., Kern S. E., Vogelstein B., Cantor A. B., Look A. T., Brodeur G. M. Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas. Cancer Res. 1992 Apr 1;52(7):1780–1785. [PubMed] [Google Scholar]
  5. Galaktionov K., Chen X., Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc. Nature. 1996 Aug 8;382(6591):511–517. doi: 10.1038/382511a0. [DOI] [PubMed] [Google Scholar]
  6. Hosoi G., Hara J., Okamura T., Osugi Y., Ishihara S., Fukuzawa M., Okada A., Okada S., Tawa A. Low frequency of the p53 gene mutations in neuroblastoma. Cancer. 1994 Jun 15;73(12):3087–3093. doi: 10.1002/1097-0142(19940615)73:12<3087::aid-cncr2820731230>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  7. Imamura J., Bartram C. R., Berthold F., Harms D., Nakamura H., Koeffler H. P. Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification. Cancer Res. 1993 Sep 1;53(17):4053–4058. [PubMed] [Google Scholar]
  8. Iwamoto T., Taniguchi M., Wajjwalku W., Nakashima I., Takahashi M. Neuroblastoma in a transgenic mouse carrying a metallothionein/ret fusion gene. Br J Cancer. 1993 Mar;67(3):504–507. doi: 10.1038/bjc.1993.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jacks T., Fazeli A., Schmitt E. M., Bronson R. T., Goodell M. A., Weinberg R. A. Effects of an Rb mutation in the mouse. Nature. 1992 Sep 24;359(6393):295–300. doi: 10.1038/359295a0. [DOI] [PubMed] [Google Scholar]
  10. Jacks T., Shih T. S., Schmitt E. M., Bronson R. T., Bernards A., Weinberg R. A. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994 Jul;7(3):353–361. doi: 10.1038/ng0794-353. [DOI] [PubMed] [Google Scholar]
  11. Johnson M. R., Look A. T., DeClue J. E., Valentine M. B., Lowy D. R. Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5539–5543. doi: 10.1073/pnas.90.12.5539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996 Oct 18;87(2):159–170. doi: 10.1016/s0092-8674(00)81333-1. [DOI] [PubMed] [Google Scholar]
  13. Kohl N. E., Gee C. E., Alt F. W. Activated expression of the N-myc gene in human neuroblastomas and related tumors. Science. 1984 Dec 14;226(4680):1335–1337. doi: 10.1126/science.6505694. [DOI] [PubMed] [Google Scholar]
  14. Kohl N. E., Kanda N., Schreck R. R., Bruns G., Latt S. A., Gilbert F., Alt F. W. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell. 1983 Dec;35(2 Pt 1):359–367. doi: 10.1016/0092-8674(83)90169-1. [DOI] [PubMed] [Google Scholar]
  15. Koike K., Jay G., Hartley J. W., Schrenzel M. D., Higgins R. J., Hinrichs S. H. Activation of retrovirus in transgenic mice: association with development of olfactory neuroblastoma. J Virol. 1990 Aug;64(8):3988–3991. doi: 10.1128/jvi.64.8.3988-3991.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Manohar C. F., Salwen H. R., Brodeur G. M., Cohn S. L. Co-amplification and concomitant high levels of expression of a DEAD box gene with MYCN in human neuroblastoma. Genes Chromosomes Cancer. 1995 Nov;14(3):196–203. doi: 10.1002/gcc.2870140307. [DOI] [PubMed] [Google Scholar]
  17. Matthay K. K. Neuroblastoma: a clinical challenge and biologic puzzle. CA Cancer J Clin. 1995 May-Jun;45(3):179–192. doi: 10.3322/canjclin.45.3.179. [DOI] [PubMed] [Google Scholar]
  18. Mohapatra G., Kim D. H., Feuerstein B. G. Detection of multiple gains and losses of genetic material in ten glioma cell lines by comparative genomic hybridization. Genes Chromosomes Cancer. 1995 Jun;13(2):86–93. doi: 10.1002/gcc.2870130203. [DOI] [PubMed] [Google Scholar]
  19. Nakamura T., Iwamura Y., Kaneko M., Nakagawa K., Kawai K., Mitamura K., Futagawa T., Hayashi H. Deletions and rearrangements of the retinoblastoma gene in hepatocellular carcinoma, insulinoma and some neurogenic tumors as found in a study of 121 tumors. Jpn J Clin Oncol. 1991 Oct;21(5):325–329. [PubMed] [Google Scholar]
  20. Piper J., Rutovitz D., Sudar D., Kallioniemi A., Kallioniemi O. P., Waldman F. M., Gray J. W., Pinkel D. Computer image analysis of comparative genomic hybridization. Cytometry. 1995 Jan 1;19(1):10–26. doi: 10.1002/cyto.990190104. [DOI] [PubMed] [Google Scholar]
  21. Ramsay G., Stanton L., Schwab M., Bishop J. M. Human proto-oncogene N-myc encodes nuclear proteins that bind DNA. Mol Cell Biol. 1986 Dec;6(12):4450–4457. doi: 10.1128/mcb.6.12.4450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Reiter J. L., Brodeur G. M. High-resolution mapping of a 130-kb core region of the MYCN amplicon in neuroblastomas. Genomics. 1996 Feb 15;32(1):97–103. doi: 10.1006/geno.1996.0081. [DOI] [PubMed] [Google Scholar]
  23. Rosenbaum H., Webb E., Adams J. M., Cory S., Harris A. W. N-myc transgene promotes B lymphoid proliferation, elicits lymphomas and reveals cross-regulation with c-myc. EMBO J. 1989 Mar;8(3):749–755. doi: 10.1002/j.1460-2075.1989.tb03435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schwab M., Alitalo K., Klempnauer K. H., Varmus H. E., Bishop J. M., Gilbert F., Brodeur G., Goldstein M., Trent J. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature. 1983 Sep 15;305(5931):245–248. doi: 10.1038/305245a0. [DOI] [PubMed] [Google Scholar]
  25. Schwab M., Varmus H. E., Bishop J. M. Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture. Nature. 1985 Jul 11;316(6024):160–162. doi: 10.1038/316160a0. [DOI] [PubMed] [Google Scholar]
  26. Skalnik D. G., Dorfman D. M., Williams D. A., Orkin S. H. Restriction of neuroblastoma to the prostate gland in transgenic mice. Mol Cell Biol. 1991 Sep;11(9):4518–4527. doi: 10.1128/mcb.11.9.4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Small J. A., Khoury G., Jay G., Howley P. M., Scangos G. A. Early regions of JC virus and BK virus induce distinct and tissue-specific tumors in transgenic mice. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8288–8292. doi: 10.1073/pnas.83.21.8288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Small M. B., Hay N., Schwab M., Bishop J. M. Neoplastic transformation by the human gene N-myc. Mol Cell Biol. 1987 May;7(5):1638–1645. doi: 10.1128/mcb.7.5.1638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. The I., Murthy A. E., Hannigan G. E., Jacoby L. B., Menon A. G., Gusella J. F., Bernards A. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat Genet. 1993 Jan;3(1):62–66. doi: 10.1038/ng0193-62. [DOI] [PubMed] [Google Scholar]
  30. Tlsty T. D. Normal diploid human and rodent cells lack a detectable frequency of gene amplification. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3132–3136. doi: 10.1073/pnas.87.8.3132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Weith A., Martinsson T., Cziepluch C., Brüderlein S., Amler L. C., Berthold F., Schwab M. Neuroblastoma consensus deletion maps to 1p36.1-2. Genes Chromosomes Cancer. 1989 Nov;1(2):159–166. doi: 10.1002/gcc.2870010209. [DOI] [PubMed] [Google Scholar]
  32. White P. S., Maris J. M., Beltinger C., Sulman E., Marshall H. N., Fujimori M., Kaufman B. A., Biegel J. A., Allen C., Hilliard C. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5520–5524. doi: 10.1073/pnas.92.12.5520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wright J. A., Smith H. S., Watt F. M., Hancock M. C., Hudson D. L., Stark G. R. DNA amplification is rare in normal human cells. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1791–1795. doi: 10.1073/pnas.87.5.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]

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