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Oncogenes, Fusion Genes and Tumor Suppressor Genes

FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells

Leukemia volume 21, pages 2476–2484 (2007)Cite this article

Abstract

Deregulated accumulation of nuclear β-catenin enhances transcription of β-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 β-catenin-dependent nuclear signaling. Tyrosine phosphorylation of β-catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and β-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 β-catenin. Although β-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 β-catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of β-catenin. Endogenous β-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant β-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of β-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces β-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and β-catenin oncogeneic signaling in AML.

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Acknowledgements

We thank Dr Kazutaka Ozeki, Nagoya University School of Medicine, for his help in preparing MOLM-13 cells and stably transfected 32D cell lines. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Support was also provided to TK by the Sumitomo Life Social Welfare Sciences Foundation. Statement of authorship: TK, LN, MJL, JBT designed research , TK, EJC, MJL, SL, AS performed research, TK wrote the paper, and HK, MJL, TN contributed vital new reagents.

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Authors and Affiliations

  1. Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    T Kajiguchi & L Neckers

  2. Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    E J Chung, S Lee & J B Trepel

  3. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

    A Stine & M J Levis

  4. Department of Infectious Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Kajiguchi & H Kiyoi

  5. Department of Hematology Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Naoe

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  1. T Kajiguchi
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Correspondence to T Kajiguchi.

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Kajiguchi, T., Chung, E., Lee, S. et al. FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia 21, 2476–2484 (2007). https://doi.org/10.1038/sj.leu.2404923

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