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Blood, 1 July 2005, Vol. 106, No. 1, pp. 265-273. Prepublished online as a Blood First Edition Paper on March 15, 2005; DOI 10.1182/blood-2004-07-2942. This Article Full Text (PDF) All Versions of this Article: 2004-07-2942v1 106/1/265    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 Choudhary, C. Articles by Serve, H. Search for Related Content PubMed PubMed Citation Articles by Choudhary, C. Articles by Serve, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 30, 2004 Accepted February 27, 2005 AML-associated Flt3 kinase domain mutations show signal transduction differences in comparison to Flt3 ITD mutations Chunaram Choudhary, Joachim Schwable, Christian Brandts, Lara Tickenbrock, Bulent Sargin, Thomas Kindler, Thomas Fischer, Wolfgang E Berdel, Carsten Muller-Tidow, and Hubert Serve* Department of Medicine, Hematology/Oncology and the Interdisciplinary Center for Clinical Research, University of Munster, Munster, Germany 3rd Med Department, Johannes-Gutenberg University, Mainz, Germany * Corresponding author; email: serve{at}uni-muenster.de. Activating mutations of Flt3 are found in approximately one third of AML patients and are an attractive drug target. Two classes of Flt3 mutations occur: Internal tandem duplications (ITD) in the juxtamembrane and point mutations in the tyrosine kinase domain (TKD). We and others have shown that Flt3-ITD induced aberrant signaling including strong STAT5 activation and repression of c/EBP and Pu.1. Here, we compared the signaling properties of Flt3-ITD versus Flt3-TKD in myeloid progenitor cells. We demonstrate that Flt3-TKD mutations induced autonomous growth of 32D cells in suspension cultures. However, in contrast to Flt3-ITD and similar to wild-type Flt3 (Flt3-WT), Flt3-TKD cannot support colony formation in semisolid media. Also in contrast to Flt3-ITD, neither Flt3-WT nor Flt3-TKD induced activation or induction of STAT5 target genes. Flt3-TKD also failed to repress c/EBP and Pu.1. No significant differences were observed in receptor autophosphorylation, and the phosphorylation of Erk-1 and 2, Akt and Shc. Importantly, TKD but not ITD mutations were a log power more sensitive towards the tyrosine kinase inhbitor PKC412 than Flt3-WT. In conclusion, Flt3-ITD and Flt3-TKD mutations display profound differences in their signaling properties that could have important implications for their transforming capacity and for the design of mutation-specific therapeutic approaches. 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] S. Meshinchi and F. R. Appelbaum Structural and Functional Alterations of FLT3 in Acute Myeloid Leukemia Clin. Cancer Res., July 1, 2009; 15(13): 4263 - 4269. [Abstract] [Full Text] [PDF] K. W. Pratz, J. Cortes, G. J. Roboz, N. Rao, O. Arowojolu, A. Stine, Y. Shiotsu, A. Shudo, S. Akinaga, D. Small, et al. 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