1. ¹Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2. ²Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
3. ³Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
4. ⁴Department of Infectious Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan
5. ⁵Department of Hematology Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Correspondence: Dr T Kajiguchi, Department of Infectious Disease, Nagoya University Graduate School of medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail: tomokaji@med.nagoya-u.ac.jp

Received 10 May 2007; Revised 7 July 2007; Accepted 23 July 2007; Published online 13 September 2007.

Abstract

Deregulated accumulation of nuclear -catenin enhances transcription of -catenin target genes and promotes malignant transformation. Recently, acute myeloid leukemia (AML) cells with activating mutations of FMS-like tyrosine kinase-3 (FLT3) were reported to display elevated -catenin-dependent nuclear signaling. Tyrosine phosphorylation of -catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and -catenin nuclear localization. Compared to cells with wild-type FLT3 (FLT3-WT), cells with the FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) had elevated levels of tyrosine-phosphorylated -catenin. Although -catenin was localized mainly in the cytoplasm in FLT3-WT cells, it was primarily nuclear in FLT3-ITD cells. Treatment with FLT3 kinase inhibitors or FLT3 silencing with RNAi decreased -catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of -catenin. Endogenous -catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant -catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of -catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces -catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and -catenin oncogeneic signaling in AML.