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

Richard Sharp, Juan A. Recio, Chamelli Jhappan, Toshiyuki Otsuka, Shiquan Liu, Yanlin Yu, Wenjing Liu, Miriam Anver, Fariba Navid, Lee J. Helman, Ronald A. DePinho, Glenn Merlino

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129 Scopus citations

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 INK40/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.

Original languageEnglish (US)
Pages (from-to)1276-1280
Number of pages5
JournalNature Medicine
Volume8
Issue number11
DOIs
StatePublished - Nov 1 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sharp, R., Recio, J. A., Jhappan, C., Otsuka, T., Liu, S., Yu, Y., Liu, W., Anver, M., Navid, F., Helman, L. J., DePinho, R. A., & Merlino, G. (2002). Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nature Medicine, 8(11), 1276-1280. https://doi.org/10.1038/nm787