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Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin

Oncogene volume 23, pages 6541–6547 (2004)Cite this article

Abstract

Previously, we have mimicked human neurofibromatosis type 2 (NF2) in conditional Nf2 mutant (P0Cre;Nf2flox2/flox2) mice. Schwannomas, characteristic for NF2, were found at low frequency in older mice. Here, we report that these mice, upon additional hemizygosity for p53, rapidly develop multiple tumours showing features consistent with malignant peripheral nerve sheath tumours. Thus, p53 hemizygosity promotes tumorigenesis of mutant Nf2 peripheral nerve cells. In contrast, young P0Cre;Nf2flox2/+;p53+/− cis mice mainly succumb to Nf2/p53-related osteogenic tumours. Therefore, Cre-mediated early biallelic loss of Nf2 function in neural crest-derived cells hemizygous for p53 results in resistance to osteogenic tumours and increased susceptibility to peripheral nerve sheath tumours.

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Acknowledgements

We thank L.A. Donehower for the p53−/− mice; F. van der Ahé, K. Ankama, N. Bosnie, T. Maidment, H. Raasø, L. Rijswijk, and A. Zwerver for animal care; the CDTA (Orléans, France) for housing part of the mouse colony; R. Regnerus for genotyping of the mice; J. Bulthuis, K. de Goeij, D. Hoogervorst, L. Kuijper-Pietersma, and E. van Muylwijk for histotechnical assistance; R. Erlandson for electron microscopy; H. te Riele for critically reading the manuscript. This work was supported by Grants from the Commission of the European Communities (BMH4-CT96-1518), Ligue Nationale Française contre le Cancer, Association pour la Recherche sur le Cancer, Human Frontier Science Program (M.G.). United States Army Medical Research and Material Command Grant DAMD 17-00-0594 (M.G.).

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Author notes

  1. Els Robanus-Maandag

    Present address: Center for Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands

  2. Els Robanus-Maandag and Marco Giovannini: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Els Robanus-Maandag & Anton Berns

  2. INSERM U434, Fondation Jean Dausset-CEPH, 27 rue Juliette Dodu, Paris, 75010, France

    Marco Giovannini, Michiko Niwa-Kawakita, Vincent Abramowski & Gilles Thomas

  3. Department of Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Martin van der Valk

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, NY, USA

    Cristina Antonescu

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  1. Els Robanus-Maandag
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Correspondence to Anton Berns.

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Robanus-Maandag, E., Giovannini, M., van der Valk, M. et al. Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin. Oncogene 23, 6541–6547 (2004). https://doi.org/10.1038/sj.onc.1207858

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