Dataset Information

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

ABSTRACT: The FLT3 tyrosine kinase receptor is involved in both hematopoiesis and hematological malignancies. The Wnt/?-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 ?-catenin by inhibition of GSK-3? in a PI3 kinase pathway-dependent manner. Ectopic expression of a dominant negative form of GSK-3? in FLT3-ITD-expressing cells activated ?-catenin and blocked the downregulation of the TCF/?-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-3? and restored by knockdown of either TCF4 or ?-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/?-catenin pathway in the cells harboring FLT3-ITD mutations, and FLT3-ITDs signal through GSK-3? to activate ?-catenin that this is likely to directly contribute to the leukemic phenotype.

SUBMITTER: Jiang J

PROVIDER: S-EPMC3092187 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

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

Jiang Jingrui J Griffin James D JD

Genes & cancer 20100201 2

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 inhib ...[more]

PMID: 21779446

Similar Datasets

Project description:Purpose: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKI) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the antileukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML.Experimental Design: Wnt/β-catenin signaling was inhibited by the β-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib. Treatments on apoptosis, cell growth, and cell signaling were assessed in cell lines, patient samples, and in vivo in immunodeficient mice by flow cytometry, Western blot, RT-PCR, and CyTOF.Results: We found significantly higher β-catenin expression in cytogenetically unfavorable and relapsed AML patient samples and in the bone marrow-resident leukemic cells compared with circulating blasts. Disrupting Wnt/β-catenin signaling suppressed AML cell growth, induced apoptosis, abrogated stromal protection, and synergized with TKIs in FLT3-mutated AML cells and stem/progenitor cells in vitro The aforementioned combinatorial treatment improved survival of AML-xenografted mice in two in vivo models and impaired leukemia cell engraftment. Mechanistically, the combined inhibition of Wnt/β-catenin and FLT3 cooperatively decreased nuclear β-catenin and the levels of c-Myc and other Wnt/β-catenin and FLT3 signaling proteins. Importantly, β-catenin inhibition abrogated the microenvironmental protection afforded the leukemic stem/progenitor cells.Conclusions: Disrupting Wnt/β-catenin signaling exerts potent activities against AML stem/progenitor cells and synergizes with FLT3 inhibition in FLT3-mutant AML. These findings provide a rationale for clinical development of this strategy for treating FLT3-mutated AML patients. Clin Cancer Res; 24(10); 2417-29. ©2018 AACR.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets