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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2498-2505. Prepublished online as a Blood First Edition Paper on June 16, 2005; DOI 10.1182/blood-2004-12-4840. This Article Full Text (PDF) All Versions of this Article: 2004-12-4840v1 106/7/2498    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Du, Y. Articles by Copeland, N. G Search for Related Content PubMed PubMed Citation Articles by Du, Y. Articles by Copeland, N. G Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 20, 2004 Accepted May 25, 2005 Cooperating cancer gene identification via oncogenic retrovirus-induced insertional mutagenesis Yang Du, Sally E Spence, Nancy A Jenkins, and Neal G Copeland* Mouse Cancer Genetics Program, National Cancer Institute, Center for Cancer Research, Frederick, MD, USA * Corresponding author; email: copeland{at}ncifcrf.gov. Multiple cooperating mutations that deregulate different signalling pathways are required to induce cancer. Identifying these cooperating mutations is a prerequisite for developing better combinatorial therapies for treating cancer. Here we show that cooperating cancer mutations can be identified via defective oncogenic retrovirus-induced insertional mutagenesis. Among thirteen myeloid leukemias induced by transplanting mice with bone marrow cells infected in vitro with a replication defective retrovirus carrying the Sox4 oncogene, nine contained insertional mutations at known or suspected cancer genes. This likely occurs because rare bone marrow cells in which the oncogenic retrovirus happens to integrate and mutate a cooperating cancer gene are selected in the transplanted host by virtue of the fact that they harbor a cooperating cancer mutation. Cooperativity between Sox4 and one gene, Mef2c, was subsequently confirmed in transplant studies, in which deregulated Mef2c expression was shown to accelerate the myeloid leukemia induced by Sox4. Insertional mutagenesis of cooperating cancer genes by a defective oncogenic retrovirus provides a new method for identifying cooperating cancer genes and could aid in the development of better therapies for treating cancer. 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