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Blood, 15 July 2007, Vol. 110, No. 2, pp. 686-694. Prepublished online as a Blood First Edition Paper on March 26, 2007; DOI 10.1182/blood-2006-10-053181. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-053181v1 110/2/686    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 Vempati, S. Articles by Spiekermann, K. Search for Related Content PubMed PubMed Citation Articles by Vempati, S. Articles by Spiekermann, K. Related Collections Neoplasia Oncogenes and Tumor Suppressors Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Sridhar Vempati1,2, Carola Reindl1,2, Seshu Kumar Kaza1, Ruth Kern1,2, Theodora Malamoussi1,2, Martin Dugas3, Gudrun Mellert4, Susanne Schnittger5, Wolfgang Hiddemann1,2, and Karsten Spiekermann1,2,4 1 Clinical Cooperative Group "Leukemia," GSF (National Research Center for Environment and Health), Munich; 2 Department of Medicine III, University of Munich-Grosshadern; 3 Institute of Medical Informatics and Biomathematics, University of Münster; 4 Laboratory for Leukemia Diagnostics, University of Munich-Grosshadern; 5 Munich Leukemia Laboratory, Germany FLT3–internal tandem duplications (FLT3-ITDs) comprise a heterogeneous group of mutations in patients with acute leukemias that are prognostically important. To characterize the mechanism of transformation by FLT3-ITDs, we sequenced the juxtamembrane region (JM) of FLT3 from 284 patients with acute leukemias. The length of FLT3-ITDs varied from 2 to 42 amino acids (AAs) with a median of 17 AAs. The analysis of duplicated AAs showed that in the majority of patients, the duplications localize between AAs 591 to 599 (YVDFREYEY). Arginine 595 (R595) within this region is duplicated in 77% of patients. Single duplication of R595 in FLT3 conferred factor-independent growth to Ba/F3 cells and activated STAT5. Moreover, deletion or substitution of the duplicated R595 in 2 FLT3-ITD constructs as well as the deletion of wild-type R595 in FLT3-ITD substantially reduced the transforming potential and STAT5 activation, pointing to a critical role of the positive charge of R595 in stabilizing the active confirmation of FLT3-ITDs. Deletion of R595 in FLT3-WT nearly abrogated the ligand-dependent activation of FLT3-WT. Our data provide important insights into the molecular mechanism of transformation by FLT3-ITDs and show that duplication of R595 is important for the leukemic potential of FLT3-ITDs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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]

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