Wnt/β-catenin Pathway Modulates the Sensitivity of the Mutant FLT3 Receptor Kinase Inhibitors in a GSK-3β Dependent Manner

The FLT3 tyrosine kinase receptor is involved in both hematopoiesis and hematological malignancies. The Wnt/β-catenin pathway has been shown to participate in the self-renewal of hematopoietic stem cells and to cooperate with the mutant FLT3 receptors in leukemic transformation. However, the detailed biological impact of such a constitutively activated Wnt pathway remains to be further explored. Here, the authors report that activating mutations of FLT3 constitutively activate β-catenin by inhibition of GSK-3β in a PI3 kinase pathway-dependent manner. Ectopic expression of a dominant negative form of GSK-3β in FLT3-ITD-expressing cells activated β-catenin and blocked the downregulation of the TCF/β-catenin transcriptional activity induced by inhibition of FLT3 kinase. Furthermore, inhibition of cell proliferation and colony formation induced by such suppression of FLT3 kinase activity could be partially reversed by knockdown of GSK-3β and restored by knockdown of either TCF4 or β-catenin. Moreover, exogenous activation of the Wnt pathway also attenuated such inhibitory effect. These findings indicate that the potencies of the inhibitors of FLT3 kinase activity could be modulated by the activity of the Wnt/β-catenin pathway in the cells harboring FLT3-ITD mutations, and FLT3-ITDs signal through GSK-3β to activate β-catenin that this is likely to directly contribute to the leukemic phenotype.