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MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells

Oncogene volume 32, pages 1059–1065 (2013)Cite this article

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Abstract

Neuroblastoma is an embryonal tumor with a heterogeneous clinical course. The tumor is presumed to be derived from the neural crest, but the cells of origin remain to be determined. To date, few recurrent genetic changes contributing to neuroblastoma formation, such as amplification of the MYCN oncogene and activating mutations of the ALK oncogene, have been identified. The possibility to model neuroblastoma in mice allows investigation of the cell of origin hypothesis in further detail. Here we present the evidence that murine neural crest progenitor cells can give rise to neuroblastoma upon transformation with MYCN or ALKF1174L. For this purpose we used JoMa1, a multipotent neural crest progenitor cell line, which is kept in a viable and undifferentiated state by a tamoxifen-activated c-Myc transgene (c-MycERT). Expression of MYCN or ALKF1174L, one of the oncogenic ALK variants identified in primary neuroblastomas, enabled these cells to grow independently of c-MycERT activity in vitro and caused formation of neuroblastoma-like tumors in vivo in contrast to parental JoMa1 cells and JoMa1 cells-expressing TrkA or GFP. Tumorigenicity was enhanced upon serial transplantation of tumor-derived cells, and tumor cells remained susceptible to the MYC-inhibitor, NBT-272, indicating that cell growth depended on functional MYCN. Our findings support neural crest progenitor cells as the precursor cells of neuroblastoma, and indicate that neuroblastomas arise as their malignant progeny.

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Acknowledgements

We thank E Mahlow, S Dreesmann, A Odersky and M Baumann for their excellent technical assistance and K Astrahantseff for proof reading the manuscript. This work was supported by the German National Genome Research Network (NGFN plus grant no. PKN-01GS0894-6 to JHS, AE and AS) and by the German Cancer Aid (grant no. 108941 to JHS and AE).

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Authors and Affiliations

  1. Department of Pediatric Oncology and Haematology, University Children’s Hospital Essen, Essen, Germany

    J H Schulte, S Lindner, A Bohrer, S Schulte, T Thor, A Künkele, A Eggert & A Schramm

  2. Department of Developmental Pathology, Institute of Pathology, University of Bonn, Bonn, Germany

    J Maurer & H Schorle

  3. Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, Ghent, Belgium

    K De Preter, S Lefever, J Vandesompele & F Speleman

  4. Department of Pathology, University of Bonn, Bonn, Germany

    L Heukamp

  5. Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    J Molenaar & R Versteeg

  6. These authors contributed equally to this work,

    S Lindner & A Bohrer

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  1. J H Schulte
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Correspondence to J H Schulte.

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Schulte, J., Lindner, S., Bohrer, A. et al. MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells. Oncogene 32, 1059–1065 (2013). https://doi.org/10.1038/onc.2012.106

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