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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-03-0936. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-03-0936v1 100/12/4154    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 December 2002, Vol. 100, No. 12, pp. 4154-4161 NEOPLASIA Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations Rui Zheng, Alan D. Friedman, and Donald Small From the Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD. Internal tandem duplication (ITD) mutations of the juxtamembrane domain-coding sequence of the FLT3 gene are found in up to 34% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. FLT3/ITDs result in constitutive activation of the tyrosine kinase domain and transform growth factor-dependent cell lines. FLT3 activation leads to antiapoptotic and proliferative signals, but little is known about the impact of FLT3/ITDs on differentiation. This study was designed to investigate the effect of FLT3/ITD expression on the differentiation of the 32Dcl3 (32D) myeloblastic cell line to neutrophils in response to granulocyte colony-stimulating factor (G-CSF). Expression of FLT3/ITD completely blocked morphologic differentiation and induction of myeloperoxidase (MPO), lysozyme, and CCAAT/enhancer-binding protein  (C/EBP) in response to G-CSF. Wild-type FLT3 and vector-transfected 32D cells were able to differentiate, although the maturation of FLT3-transfected cells was delayed by FLT3 ligand (FL) stimulation. CEP-701, a potent FLT3 tyrosine kinase inhibitor, overcame the morphologic block in differentiation caused by FLT3/ITD expression and allowed G-CSF induction of myeloid maturation markers. These findings suggest that blocking differentiation may be one of the mechanisms by which FLT3/ITDs contribute to leukemogenesis. CEP-701 and other FLT3 inhibitors may be useful for overcoming the block to differentiation (as well as the block to apoptosis) in the leukemic cells of patients with AML. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H.-G. Kim, K. Kojima, C. S. Swindle, C. V. Cotta, Y. Huo, V. Reddy, and C. A. Klug FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia Blood, February 1, 2008; 111(3): 1567 - 1574. [Abstract] [Full Text] [PDF] C. Yeamans, D. Wang, I. Paz-Priel, B. E. Torbett, D. G. Tenen, and A. D. Friedman C/EBP{alpha} binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment Blood, November 1, 2007; 110(9): 3136 - 3142. [Abstract] [Full Text] [PDF] Q. Yao, B. Weigel, and J. 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	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020