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

T. Kajiguchi, E. J. Chung, S. Lee, A. Stine, H. Kiyoi, T. Naoe, M. J. Levis, L. Neckers, J. B. Trepel

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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.

Original languageEnglish (US)
Pages (from-to)2476-2484
Number of pages9
JournalLeukemia
Volume21
Issue number12
DOIs
StatePublished - Dec 2007

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Kajiguchi, T., Chung, E. J., Lee, S., Stine, A., Kiyoi, H., Naoe, T., Levis, M. J., Neckers, L., & Trepel, J. B. (2007). FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia, 21(12), 2476-2484. https://doi.org/10.1038/sj.leu.2404923