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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2107-2114. Prepublished online as a Blood First Edition Paper on November 9, 2004; DOI 10.1182/blood-2004-03-0940. This Article Full Text (PDF) All Versions of this Article: 2004-03-0940v1 105/5/2107    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 Schwable, J. Articles by Serve, H. Search for Related Content PubMed PubMed Citation Articles by Schwable, J. Articles by Serve, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 11, 2004 Accepted October 7, 2004 RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation Joachim Schwable, Chunaram Choudhary, Christian Thiede, Lara Tickenbrock, Bulent Sargin, Claudia Steur, Maike Rehage, Annika Rudat, Christian Brandts, Wolfgang E Berdel, Carsten Muller-Tidow, and Hubert Serve* Department of Medicine, Hematology and Oncology, University of Munster, Muenster, Germany Medizinische Klinik und Poliklinik I, Universitatsklinikum Carl Gustav Carus der Technischen Universitat, Dresden, Germany * Corresponding author; email: serve{at}uni-muenster.de. Activating Flt3 mutations represent the most common genetic aberrations in acute myeloid leukemia (AML). Most commonly, they occur as internal tandem duplications in the juxtamembrane domain (Flt3-ITD) that transform myeloid cells in vitro and in vivo and that induce aberrant signaling and biologic functions. We identified RGS2, a regulator of G-protein signaling, as a gene specifically repressed by Flt3-ITD. Here, we demonstrate an important role of RGS2 in Flt3-ITD mediated transformation. RGS2 was repressed after forced expression of activating Flt3 mutations in two myeloid cell lines (32Dcl3 and NB4). Furthermore, RGS-2 was repressed in Flt3-mutation-positive AML cases in comparison to Flt3-mutation-negative cases, especially in Flt3-ITD-positive cases with a high ITD to WT ratio. Coexpression of RGS2 with Flt3-ITD inhibited Flt3-ITD induced autonomous proliferation and clonal growth of 32D cells. RGS2 also inhibited Flt3-ITD induced phosphorylation of Akt and Gsk3-beta without influencing STAT5 activation. In addition, RGS2 re-induced the expression of Flt3-ITD-repressed c/EBPalpha and antagonized the Flt3-ITD-induced differentiation block in 32D cells. Expression analyses in myeloid cell lines revealed induction of RGS2 during granulocytic but not during monocytic differentiation. Taken together, RGS2 is a novel mediator of myeloid differentiation and its repression is an important event in Flt3-ITD induced transformation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. Jonsson BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3 Blood, March 5, 2009; 113(10): 2302 - 2311. [Abstract] [Full Text] [PDF] E. Bulk, B. Sargin, U. Krug, A. Hascher, Y. Jun, M. Knop, C. Kerkhoff, V. Gerke, R. 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