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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1339-1345. Prepublished online as a Blood First Edition Paper on April 25, 2006April 20, 2006; DOI 10.1182/blood-2005-11-011429. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2005-11-011429v1 blood-2005-11-011429v2 108/4/1339    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 Rocnik, J. L Articles by Gilliland, D G. Search for Related Content PubMed PubMed Citation Articles by Rocnik, J. L Articles by Gilliland, D G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 21, 2005 Accepted April 2, 2006 Roles of Tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD Jennifer L Rocnik*, Rachel Okabe, Jin-Chen Yu, Neill Giese, David P Schenkein, and D Gary Gilliland Brigham and Women's Hospital and Harvard Medical School, Boston, MA Millenium Pharmaceuticals, Cambridge, MA * Corresponding author; email: jrocnik{at}rics.bwh.harvard.edu. Acquired mutations in the FLT3 receptor tyrosine kinase are common in acute myeloid leukemia, and result in constitutive activation. The most frequent mechanism of activation is disruption of the juxtamembrane autoregulatory domain by internal tandem duplications (ITDs). FLT3-ITDs confer factor independent growth to hematopoietic cells, and induce a myeloproliferative syndrome in murine bone marrow transplant models. We, and others, have observed that FLT3-ITD activates STAT5 and its downstream effectors, whereas ligand stimulated wild type FLT3 (FLT3WT) does not. In vitro mapping of tyrosine phosphorylation sites in FLT3-ITD identified two candidate STAT5 docking sites within the juxtamembrane domain that is disrupted by the ITD. Tyrosine to phenylalanine substitution of residues 589 and 591 in the context of the FLT3-ITD did not affect tyrosine kinase activity, but abrogated STAT5 activation. Furthermore, FLT3-ITD Y589/591F was incapable of inducing a myeloproliferative phenotype when transduced into primary murine bone marrow cells, whereas FLT3-ITD induced myeloproliferative disease with a median latency of 50 days. Thus, the conformational change in the FLT3 juxtamembrane domain induced by the ITD activates the kinase through dysregulation of autoinhibition, and results in qualitative differences in signal transduction through STAT5 that are essential for the transforming potential of FLT3-ITD in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Kayser, R. F. Schlenk, M. C. Londono, F. Breitenbuecher, K. Wittke, J. Du, S. Groner, D. Spath, J. Krauter, A. Ganser, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome Blood, September 17, 2009; 114(12): 2386 - 2392. [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] F. Breitenbuecher, B. Markova, S. Kasper, B. Carius, T. Stauder, F. D. Bohmer, K. Masson, L. Ronnstrand, C. Huber, T. Kindler, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML Blood, April 23, 2009; 113(17): 4063 - 4073. [Abstract] [Full Text] [PDF] S. Vempati, C. Reindl, U. Wolf, R. Kern, K. Petropoulos, V. M. Naidu, C. Buske, W. Hiddemann, T. M. Kohl, and K. Spiekermann Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591 Clin. Cancer Res., July 15, 2008; 14(14): 4437 - 4445. [Abstract] [Full Text] [PDF] S. Meshinchi, D. L. Stirewalt, T. A. Alonzo, T. J. Boggon, R. B. Gerbing, J. L. Rocnik, B. J. Lange, D. G. Gilliland, and J. P. Radich Structural and numerical variation of FLT3/ITD in pediatric AML Blood, May 15, 2008; 111(10): 4930 - 4933. [Abstract] [Full Text] [PDF] E. Weisberg, L. Banerji, R. D. Wright, R. Barrett, A. Ray, D. Moreno, L. Catley, J. Jiang, E. Hall-Meyers, M. Sauveur-Michel, et al. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells Blood, April 1, 2008; 111(7): 3723 - 3734. [Abstract] [Full Text] [PDF] S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [Abstract] [Full Text] [PDF] C. Choudhary, C. Brandts, J. Schwable, L. Tickenbrock, B. Sargin, A. Ueker, F.-D. Bohmer, W. E. Berdel, C. Muller-Tidow, and H. Serve Activation mechanisms of STAT5 by oncogenic Flt3-ITD Blood, July 1, 2007; 110(1): 370 - 374. [Abstract] [Full Text] [PDF] J. M. Irish, N. Anensen, R. Hovland, J. Skavland, A.-L. Borresen-Dale, O. Bruserud, G. P. Nolan, and B. T. 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