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Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis

Nature Medicine volume 8, pages 1276–1280 (2002)Cite this article

A Corrigendum to this article was published on 01 January 2003

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf−/− mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.

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Figure 1: Selective induction of rhabdomyosarcoma (RMS) in HGF/SF-transgenic, Ink4a/Arf-deficient mice.
Figure 2: Histopathological and immunohistochemical characterization of mouse RMS.
Figure 3: Molecular analysis of mouse and human RMS.
Figure 4: Influence of c-Met activation and Ink4a/Arf loss on myoblast growth and differentiation.

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Notes

  1. Note: In the original version of this article published online 7 October 2002, the center lanes of each gel in Figure 4b were marked positive (+). They should have been marked negative (−). The authors regret this error. This has been corrected in the HTML version of the article and a corrigendum has been appended to the PDF version of this article. A print corrigendum will appear in a forthcoming issue of the journal.

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Acknowledgements

We thank D. Spicer, H. Takayama, G. Celli, K. Miura, P. Meltzer, L. Wakefield, G.Vande Woude and J. Ward for useful discussions; M. Tsokos for assistance with initial histopathological evaluation; J. Owens for electron microscopy; H. Wimbrow for animal colony husbandry; and B. Kasprzak and D. Butcher for immunohistochemistry. We thank the following for plasmid DNAs: G. Bell (for mouse IGF-II); B. Vogelstein (for human MDM2); Ed Harlow (for human CDK4); K. Huppi (for mouse GAPDH); E.Olson (for mouse myoD and myogenin); P. Seale (for pax7); and C. Ponzetto (for mouse myf5). This work was supported, in part, by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute, and in part by NIH U01CA84313-04. R.A.D. is an American Cancer Society Research Professor.

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Author notes

  1. Richard Sharp and Juan A. Recio: R.S. and J.A.R. contributed equally to this study.

Authors and Affiliations

  1. Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA

    Richard Sharp, Juan A. Recio, Chamelli Jhappan, Toshiyuki Otsuka, Shiquan Liu, Yanlin Yu, Wenjing Liu & Glenn Merlino

  2. Pathology/Histotechnology Laboratory, SAIC, Frederick Cancer Research and Development Center, Frederick, Maryland, USA

    Miriam Anver

  3. Pediatric Branch, National Cancer Institute, Bethesda, Maryland, USA

    Fariba Navid & Lee J. Helman

  4. Department of Adult Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Ronald A. DePinho

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Correspondence to Glenn Merlino.

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Sharp, R., Recio, J., Jhappan, C. et al. Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nat Med 8, 1276–1280 (2002). https://doi.org/10.1038/nm787

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