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

  1. Author:
    Sharp, R.
    Recio, J. A.
    Jhappan, C.
    Otsuka, T.
    Liu, S. Q.
    Yu, Y. L.
    Liu, W. J.
    Anver, M.
    Navid, F.
    Helman, L. J.
    DePinho, R. A.
    Merlino, G.

  2. Author Address

    NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA NCI, Mol Biol Lab, Bethesda, MD 20892 USA Frederick Canc Res & Dev Ctr, SAIC, Pathol Histotechnol Lab, Frederick, MD USA NCI, Pediat Branch, Bethesda, MD 20892 USA Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol Med & Genet, Boston, MA 02115 USA Merlino G NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA
    1. Year: 2002
  2. Journal: Nature Medicine
    1. 8
    2. 11
    3. Pages: 1276-1280
  4. Type of Article: Article
  1. 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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