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Blood, 23 April 2009, Vol. 113, No. 17, pp. 4074-4077. Prepublished online as a Blood First Edition Paper on May 15, 2008; DOI 10.1182/blood-2007-11-125476. This Article Full Text (PDF) All Versions of this Article: blood-2007-11-125476v1 113/17/4074    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 Breitenbuecher, F. Articles by Fischer, T. Search for Related Content PubMed PubMed Citation Articles by Breitenbuecher, F. Articles by Fischer, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 26, 2007 Accepted April 19, 2008 Identification of a novel type of ITD mutations located in non-juxtamembrane domains of the FLT3 tyrosine kinase receptor Frank Breitenbuecher, Susanne Schnittger, Rebekka Grundler, Boyka Markova, Birgit Carius, Alexandra Brecht, Justus Duyster, Torsten Haferlach, Christoph Huber, and Thomas Fischer* 3rd Medical Department, Johannes Gutenberg-University, Mainz, Germany MLL Munich Leukemia Laboratory, Munich, Germany Department of Internal Medicine III, Technical University of Munich, Munich, Germany * Corresponding author; email: t.fischer{at}3-med.klinik.uni-mainz.de. In AML, internal tandem duplications (ITDs) of the juxtamembrane (JM) of FLT3 have been demonstrated to play a crucial role in driving proliferation and survival of the leukemic clone. Here, we report the identification of FLT3_ITD mutations located in non-JM domains of the FLT3-receptor. This novel type of FLT3_ITD mutations was found in 216 of 753 (28.7%) of unselected FLT3_ITD-positive AML cases. An FLT3 receptor harbouring a prototypic non-JM ITD (FLT3_ITD627E) mediated constitutive phosphorylation of FLT3 and of STAT5 suggesting that non-JM ITDs confer constitutive activation of the receptor. FLT3_ITD627E induced transformation of hematopoietic 32D cells and led to a lethal myeloproliferative disease in a syngeneic mouse model. Our results indicate that a significant proportion of activating FLT3_ITD mutations is not confined to the JM-domain of FLT3. Further studies are warranted to define the biological and clinical characteristics of non-JM ITDs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Fathoming Flt3 Roger Briesewitz Blood 2009 113: 3889-3890. [Full Text] [PDF] 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] R. Briesewitz Fathoming Flt3 Blood, April 23, 2009; 113(17): 3889 - 3890. [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]

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