Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells

Nature Genetics volume 12, pages 144–148 (1996)Cite this article

A Correction to this article was published on 01 April 1996

Abstract

Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1−/− mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Riccardi, V.M. & Eichner, J.E. Neurofibromatosis (Johns Hopkins University Press, Baltimore- USA, 1986).

    Google Scholar 

  2. Bader, J.L. & Miller, R.W. Neurofibromatosis and childhood leukemia. J. Pediat. 92, 925–929 (1978).

    Article  CAS  Google Scholar 

  3. Shannon, K.M. et al. Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis. Blood 79, 1311–1318 (1992).

    CAS  PubMed  Google Scholar 

  4. Gadner, H. & Haas, O.A. Experience in pediatric myelodysplastic syndromes. Hemat. Clin. N.A. 6, 655–672 (1992).

    Article  CAS  Google Scholar 

  5. Skuse, G.R., Kosciolek, B.A. & Rowley, P.T. Molecular genetic analysis of tumors in von Recklinghausen neurofibromatosis: loss of heterozygosity for chromosome 17. Genes Chrom. Cancer 1, 36–41 (1989).

    Article  CAS  Google Scholar 

  6. Menon, A.G. et al. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc. Natl. Acad. Sci. USA 87, 5435–5439 (1990).

    Article  CAS  Google Scholar 

  7. Glover, T.W. et al. Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis. Genes Chrom. Cancer 3, 62–70 (1991).

    Article  CAS  Google Scholar 

  8. Xu, W. et al. Loss of alleles in pheochromocytomas from patients with type 1 neurofibromatosis. Genes Chrom. Cancer 4, 337–341 (1992).

    Article  CAS  Google Scholar 

  9. Jacks, T. et al. Tumorigenic and developmental consequences of a targeted Nf1 mutation in the mouse. Nature Genet. 7, 353–361 (1994).

    Article  CAS  Google Scholar 

  10. Bourne, H.R., Sanders, D.A. & McCormick, F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348, 125–132 (1990).

    Article  CAS  Google Scholar 

  11. Bourne, H.R., Sanders, D.A. & McCormick, F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 349, 117–127 (1991).

    Article  CAS  Google Scholar 

  12. Hall, A. Signal transduction through small GTPases — a tale of two GAPs. Cell 69, 389–391 (1992).

    Article  CAS  Google Scholar 

  13. Boguski, M. & McCormick, F. Proteins regulating Ras and its relatives. Nature 366, 643–653 (1993).

    Article  CAS  Google Scholar 

  14. Basu, T.N. et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713–715 (1992).

    Article  CAS  Google Scholar 

  15. DeClue, J.E. et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69, 265–273 (1992).

    Article  CAS  Google Scholar 

  16. The, I. et al. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nature Genet. 3, 62–66 (1993).

    Article  CAS  Google Scholar 

  17. Andersen, L.B. et al. Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nature Genet. 3, 118–121 (1993).

    Article  CAS  Google Scholar 

  18. 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. USA 90, 5539–5545 (1993).

    Article  CAS  Google Scholar 

  19. Rodenhuis, S. Ras and human tumors. Semin. Cancer Biol. 3, 241–247 (1992).

    CAS  PubMed  Google Scholar 

  20. Noda, M., Ko, M. & Ogura, A. Sarcoma viruses carrying the ras oncogene activate differentiation-associated properties of a neuronal cell line. Nature 318, 73–75 (1985).

    Article  CAS  Google Scholar 

  21. Bar-Sagi, D. & Feramisco, J.R. Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell 42, 841–648 (1985).

    Article  CAS  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. 7, 1635–1645 (1988).

    Article  CAS  Google Scholar 

  23. Shannon, K.M. et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. New Engl. J.Med. 330, 597–601 (1994).

    Article  CAS  Google Scholar 

  24. Kalra, R., Paderanga, D., Olson, K. & Shannon, K.M. Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras. Blood 84, 3435–3439 (1994).

    CAS  PubMed  Google Scholar 

  25. Pierce, J.H. & Aaronson, S.A. Myeloid cell transformation by ras-containing murine sarcoma viruses. Mol. Cell. Biol. 5, 667–674 (1985).

    Article  CAS  Google Scholar 

  26. Kahn, P. et al. v-erbA cooperates with sarcoma oncogenes in leukemic cell transformation. Cell 45, 349–356 (1986).

    Article  CAS  Google Scholar 

  27. Bollag, G. & McCormick, F. Differential regulation of rasGAP and neurofibromatosis gene product activities. Nature 351, 576–579 (1991).

    Article  CAS  Google Scholar 

  28. Emanuel, P.D., Bates, L.J., Castleberry, R.P., Gualtieri, R.J. & Zuckerman, K.S. Seletive hypersensitivity to granulocyte-macrophage colony stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77, 925–929 (1991).

    CAS  PubMed  Google Scholar 

  29. Freedman, M.H. et al. Central role of tumor necrosis factor, GM-CSF, and interieukin 1 in the pathogenesis of juvenile chronic myelogenous leukemia. Br. J. Haemal. 80, 40–48 (1992).

    Article  CAS  Google Scholar 

  30. Brannan, C. et al. Targeted disruption of the neurofibromatosis, type 1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029 (1994).

    Article  CAS  Google Scholar 

  31. Johnson, M.R. et al. Neurofibromin can inhibit Ras-dependent growth by a mechanism independent of its GTPase-accelerating function. Mol. Cell. Biol. 14, 641–645 (1994).

    Article  CAS  Google Scholar 

  32. Marshall, C.J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    Article  CAS  Google Scholar 

  33. Neubauer, A., Shannon, K.M. & Liu, E. Mutations of the ras proto-oncogenes in childhood monosomy 7. Blood 77, 594–598 (1991).

    CAS  PubMed  Google Scholar 

  34. Miyauchi, J. et al. Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. Blood 83, 2248–2254 (1994).

    CAS  PubMed  Google Scholar 

  35. Burgering, B.M., de Vries-Smits, A.M., Medema, R.H., van Weeren, P.C., Tertoolen, L.G. & Bos, J.L. Epidermal growth factor induces phosphorylation of extracellular signal-regulated kinase 2 via multiple pathways. Mol. Cell Biol. 13, 7248–7256 (1993).

    Article  CAS  Google Scholar 

  36. Lanfrancone, L. et al. Overexpression of She proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/SOS and Grb2/p140 complexes to the β receptor subunit. Oncogene 10, 907–917 (1995).

    CAS  PubMed  Google Scholar 

  37. Satoh, T. . et al. Accumulation of p21ras·GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity. Proc. Natl. Acad. Sci. USA 87, 7926–7929 (1990).

    Article  CAS  Google Scholar 

  38. Mui, A.L.-F., Miyajima, A. lnterleukin-3 and granulocyte-macrophage colony-stimulating factor receptor signal transduction. Proc. Soc. Exp. Biol. Med. 206, 284–288 (1994).

    Article  CAS  Google Scholar 

  39. Johnson, G.R., Gonda, T.J., Metcalf, D., Hariharan, 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. 8, 441–448 (1989).

    Article  CAS  Google Scholar 

  40. Lang, R. et al. Transgenic mice expressing a hematopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage. Cell 51, 675–686 (1987).

    Article  CAS  Google Scholar 

  41. Kaneko, Y. et al. Chromosome patterns in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis. Leukemia 3, 36–41 (1989).

    CAS  PubMed  Google Scholar 

  42. Vogel, K.S., Brannan, C.I., Jenkins, N.A., Copeland, N.G. & Parada, L.F. Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell 82, 733–742 (1995).

    Article  CAS  Google Scholar 

  43. Gibbs, J.B., Oliff, A. & Kohl, N.E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77, 175–178 (1994).

    Article  CAS  Google Scholar 

  44. Downward, J., Graves, J.D., Warne, P.H., Rayter, S. & Cantrell, D.A. Stimulation of p21ras upon T-cell activation. Nature 346, 719–723 (1990).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Onyx Pharmaceuticals, 3031 Research Drive, Richmond, California, 94806, USA

    Gideon Bollag

  2. Herman B. Wells Research Center, Riley Children's Hospital, Indiana University Medical Center, 702 Barnhill, Indianapolis, Indiana, 46202, USA

    D. Wade Clapp & You Yan Zhang

  3. Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Shane Shih, Frank McCormick & Tyler Jacks

  4. Department of Pediatrics, University of California, San Francisco, California, 94143-0519, USA

    Felix Adler, Patricia Thompson & Kevin Shannon

  5. Division of Hematology Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA

    Beverly J. Lange

  6. Division of Hematology Oncology, Hospital for Sick Children, Toronto, Ontario, M5G1X8, Canada

    Melvin H. Freedman

Authors
  1. Gideon Bollag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Wade Clapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shane Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Felix Adler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. You Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patricia Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Beverly J. Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Melvin H. Freedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank McCormick
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tyler Jacks
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kevin Shannon
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bollag, G., Clapp, D., Shih, S. et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 12, 144–148 (1996). https://doi.org/10.1038/ng0296-144

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0296-144

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing