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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1883-1890. Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-06-1978. This Article Full Text (PDF) All Versions of this Article: 2003-06-1978v1 103/5/1883    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 Zheng, R. Articles by Small, D. Search for Related Content PubMed PubMed Citation Articles by Zheng, R. Articles by Small, D. Social Bookmarking                   What's this? Submitted June 18, 2003 Accepted October 24, 2003 Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBP expression Rui Zheng, Alan D Friedman, Mark Levis, Li Li, Edward G Weir, and Donald Small* Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA * Corresponding author; email: donsmall{at}jhmi.edu. Constitutively activating mutations of FLT3 occur in approximately 1/3 of patients with AML and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest which characterizes leukemia. In this report we investigated the mechanism by which FLT3/ITD signaling blocks differentiation. Normally, myeloid differentiation requires the induction of C/EBP and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/EBP and PU.1 accompanied by signs of differentiation in 2/3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/EBP was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBP in this process. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. Yamaguchi, X.-Y. Fu, and L. M. 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