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c-Myc Overexpression Causes Anaplasia in Medulloblastoma

Departments of ¹ Neuropathology and ² Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland and ³ Department of Pediatrics, Drexel University School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Duncan Stearns, Department of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Av., Baltimore, MD 21205. Phone: 410-502-5157; Fax: 410-955-9777; E-mail: steardu{at}jhmi.edu.

Both anaplasia and increased c-myc gene expression have been shown to be negative prognostic indicators for survival in medulloblastoma patients. myc gene amplification has been identified in many large cell/anaplastic medulloblastoma, but no causative link between c-myc and anaplastic changes has been established. To address this, we stably overexpressed c-myc in two medulloblastoma cell lines, DAOY and UW228, and examined the changes in growth characteristics. When analyzed in vitro, cell lines with increased levels of c-myc had higher rates of growth and apoptosis as well as significantly improved ability to form colonies in soft agar compared with control. When injected s.c. into nu/nu mice, flank xenograft tumors with high levels of c-myc in DAOY cell line background were 75% larger than those derived from control. Overexpression of c-myc was required for tumor formation by UW228 cells. Most remarkably, the histopathology of the Myc tumors was severely anaplastic, with large areas of necrosis/apoptosis, increased nuclear size, and macronucleoli. Indices of proliferation and apoptosis were also significantly higher in Myc xenografts. Thus, c-myc seems to play a causal role in inducing anaplasia in medulloblastoma. Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms. (Cancer Res 2006; 66(2): 673-81)

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