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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.
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Submitted July 28, 2004
Accepted December 14, 2004
Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction
Lara Tickenbrock, Joachim Schwable, Markus Wiedehage, Bjorn Steffen, Bulent Sargin, Chunaram Choudhary, Christian Brandts, Wolfgang E Berdel, Carsten Muller-Tidow, and Hubert Serve*
Department of Medicine, Hematology and Oncology, University of Munster, Munster, Germany
The Interdisciplinary Centre of Clinical Research Munster (IZKF), University of Munster, Munster, Germany
* Corresponding author; email: serve{at}uni-muenster.de.
Activating Flt3 mutations occur in about 30% of AML patients, 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 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 real-time RT-PCR and on the protein level. Compared to 32D/Flt3-WT 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 out of 7 AML samples with Flt3-ITD mutations expressed high -Catenin protein levels, whereas patients with wildtype Flt3 did not. Also, Flt3-ITD induced enhanced 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.
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