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Identification of OTX2 as a Medulloblastoma Oncogene Whose Product can be Targeted by All-Trans Retinoic Acid

¹ Brain Tumor Center, Department of Pathology, Duke University Medical Center, Durham, North Carolina; ² Johns Hopkins University Medical Institutions, Baltimore, Maryland; and ³ University of Utah School of Medicine, Salt Lake City, Utah

Requests for reprints: Hai Yan, Duke University Medical Center, Department of Pathology, DUMC-3156, 199A-MSRB Building, Research Drive, Durham, NC 27710. Phone: 919-668-7850; Fax: 919-684-8756; E-mail: hai.yan{at}duke.edu.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.

Key Words: OTX2 (human orthodenticle homologue 2) • digital karyotyping

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