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Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Oncogene volume 31, pages 4667–4676 (2012)Cite this article

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Abstract

Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALKdel2-3) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALKdel2-3 was autophosphorylated in NB-1 cells as well as in ALKdel2-3-transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALKdel2-3-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALKdel2-3-expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

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Acknowledgements

We thank Mrs Matsumura, Mrs Hoshino, Mrs Yin, Miss Ogino and Mrs Saito for their excellent technical assistance. We would also thank Dr Tanaka, Dr Saito, Mr Shiosaka and Mrs Mori for useful advice concerning biological analysis; Dr AT Look, Harvard Medical University, and Dr A Inoue, St Jude Children's Research Hospital, for their generous gifts of neuroblastoma cell lines. This work was supported by Research on Measures for Intractable Diseases, Health and Labor Sciences Research Grants, Ministry of Health, Labor and Welfare, Research on Health Sciences focusing on Drug Innovation, the Japan Health Sciences Foundation and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    J Okubo, J Takita, Y Chen, K Oki, R Nishimura, M Kato, M Hiwatari & T Igarashi

  2. Department of Cell Therapy and Transplantation Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    J Takita

  3. Cancer Genomics Project, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    M Sanada & S Ogawa

  4. Gunma Children's Medical Center, Maebashi, Japan

    Y Hayashi

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  1. J Okubo
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Correspondence to J Takita.

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Okubo, J., Takita, J., Chen, Y. et al. Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma. Oncogene 31, 4667–4676 (2012). https://doi.org/10.1038/onc.2011.616

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