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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-04-1045. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-04-1045v1 101/4/1494    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 Spiekermann, K. Articles by Hiddemann, W. Search for Related Content PubMed PubMed Citation Articles by Spiekermann, K. Articles by Hiddemann, W. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1494-1504 NEOPLASIA The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3 Karsten Spiekermann, Ralf J. Dirschinger, Ruth Schwab, Ksenia Bagrintseva, Florian Faber, Christian Buske, Susanne Schnittger, Louise M. Kelly, D. Gary Gilliland, and Wolfgang Hiddemann From the Department of Medicine III, University Hospital Grosshadern, Clinical Cooperative Group "Leukemia," GSF National Research Center for Environment and Health, Munich, Germany; and Howard Hughes Medical Institute and Brigham and Women's Hospital, Harvard Institutes of Medicine, Harvard Medical School, Boston, MA Activating mutations of the protein tyrosine kinase (PTK) FLT3 can be found in approximately 30% of patients with acute myeloid leukemia (AML), thereby representing the most frequent single genetic alteration in AML. These mutations occur in the juxtamembrane (FLT3 length mutations; FLT3-LMs) and the second tyrosine kinase domain of FLT3-TKD and confer interleukin 3 (IL-3)-independent growth to Ba/F3 cells. In the mouse bone marrow transplantation model, FLT3-LMs induce a myeloproliferative syndrome stressing their transforming activity in vivo. In this study, we analyzed the pro-proliferative and antiapoptotic potential of FLT3 in FLT3-LM/TKD-mutation-transformed Ba/F3 cells and AML-derived cell lines. The PTK inhibitor SU5614 has inhibitory activity for FLT3 and selectively induces growth arrest, apoptosis, and cell cycle arrest in Ba/F3 and AML cell lines expressing a constitutively activated FLT3. In addition, the compound reverts the antiapoptotic and pro-proliferative activity of FLT3 ligand (FL) in FL-dependent cells. No cytotoxic activity of SU5614 was found in leukemic cell lines that express a nonactivated FLT3 or no FLT3 protein. At the biochemical level, SU5614 down-regulated the activity of the hyperphosphorylated FLT3 receptor and its downstream targets, signal transducer and activator of (STAT) 3, STAT5, and mitogen-activated protein kinase (MAPK), and the STAT5 target genes BCL-XL and p21. Our results show that SU5614 is a PTK inhibitor of FLT3 and has antiproliferative and proapoptotic activity in AML-derived cell lines that endogenously express an activated FLT3 receptor. The selective and potent cytotoxicity of FLT3 PTK inhibitors support a clinical strategy of targeting FLT3 as a new molecular treatment option for patients with FLT3-LM/TKD-mutation+ AML. © 2003 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: M. Benekli, H. Baumann, and M. Wetzler Targeting Signal Transducer and Activator of Transcription Signaling Pathway in Leukemias J. Clin. Oncol., September 10, 2009; 27(26): 4422 - 4432. [Abstract] [Full Text] [PDF] A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. 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