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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 (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 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 March 26, 2002 Accepted July 16, 2002 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* Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA * Corresponding author; email: donsmall{at}jhmi.edu. 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 anti-apoptotic 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 G-CSF. Expression of FLT3/ITD completely blocked morphologic differentiation and induction of myeloperoxidase (MPO), lysozyme and C/EBPe 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 might be useful for overcoming the block to differentiation (as well as the block to apoptosis) in the leukemic cells of patients with AML. 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. Kersey Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51 Clin. 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