Nature Medicine8, 1276 - 1280 (2002)
Published online: 7 October 2002; | doi:10.1038/nm787
There is a Corrigendum (January 2003) associated with this Article.
Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis
Richard Sharp1, 5, Juan A. Recio1, 5, Chamelli Jhappan1, Toshiyuki Otsuka1, Shiquan Liu1, Yanlin Yu1, Wenjing Liu1, Miriam Anver2, Fariba Navid3, Lee J. Helman3, Ronald A. DePinho4
& Glenn Merlino1
1
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland, USA
2
Pathology/Histotechnology Laboratory, SAIC, Frederick Cancer Research and Development Center, Frederick, Maryland, USA
3
Pediatric Branch, National Cancer Institute, Bethesda, Maryland, USA
4
Department of Adult Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
5
R.S. and J.A.R. contributed equally to this study.
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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