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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3699-3706. Prepublished online as a Blood First Edition Paper on January 13, 2005; DOI 10.1182/blood-2004-07-2924. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2924v1 105/9/3699    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tickenbrock, L. Articles by Serve, H. Search for Related Content PubMed PubMed Citation Articles by Tickenbrock, L. Articles by Serve, H. Related Collections Hematopoiesis and Stem Cells Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction Lara Tickenbrock, Joachim Schwäble, Markus Wiedehage, Björn Steffen, Bülent Sargin, Chunaram Choudhary, Christian Brandts, Wolfgang E. Berdel, Carsten Müller-Tidow, and Hubert Serve From the Department of Medicine, Hematology, and Oncology, University of Münster, Münster, Germany; and the Interdisciplinary Centre of Clinical Research Münster (IZKF), University of Münster, Münster, Germany. Activating Flt3 mutations occur in about 30% of patients with acute myeloid leukemia (AML), often as in-frame internal tandem duplication (ITD) at the juxtamembrane domain of the receptor. These mutations transform hematopoietic cell lines and primary mouse bone marrow. Here, we analyzed the interaction between oncogenic Flt3-ITD mutations and the Wingless-type (Wnt) signaling pathway in the myeloid progenitor cell line 32D. Microarray analyses revealed higher mRNA expression of Frizzled-4, a receptor for Wnt ligands in 32D/Flt3-ITD cells. Findings were verified by quantitative realtime reverse transcription–polymerase chain reaction (RT-PCR) and on the protein level. Compared with 32D/Flt3-WT (wild-type) cells, 32D/Flt3-ITD cells also showed greatly enhanced -catenin protein levels, irrespective of their exposure to Wnt3a, a ligand inducing the canonical Wnt signal transduction pathway. In addition, 5 of 7 AML samples with Flt3-ITD mutations expressed high -catenin protein levels, whereas patients with wild-type Flt3 did not. Also, Flt3-ITD induced enhanced T-cell factor (TCF)–dependent transcriptional activity and the induction of the Wnt target gene c-myc. In the presence of Flt3-WT or Flt3-ITD signaling, Wnt3a slightly increased 32D cell proliferation. However, transfection experiments with dominant-negative (dn) TCF4 revealed a strong dependence of Flt3-ITD–mediated clonogenic growth on TCF activity. Taken together, our results indicate that Flt3-ITD and Wnt-dependent signaling pathways synergize in myeloid transformation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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