Disruption of Wnt/β-Catenin Exerts Antileukemia Activity and Synergizes with FLT3 Inhibition in FLT3 -Mutant Acute Myeloid Leukemia

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Xuejie JiangB Z Carter

Abstract

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 aforementione...Continue Reading

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Citations

Apr 14, 2019·Journal of Cellular Physiology·Jessica L HeathGary S Stein
Dec 31, 2019·The Journal of Experimental Medicine·Yoon-A KangEmmanuelle Passegué
Mar 1, 2020·Journal of Applied Toxicology : JAT·Peter C W LuLouise M Winn
Jun 24, 2020·Journal of Leukocyte Biology·Sheila C Soares-LimaFlávia R G Carneiro
Sep 3, 2020·International Journal of Molecular Sciences·Yongsheng RuanYong-Mi Kim
Feb 16, 2019·Journal of Experimental & Clinical Cancer Research : CR·Alejandro Pérez-FernándezÁngel Hernández-Hernández
Mar 21, 2020·Signal Transduction and Targeted Therapy·Dan LiJianfeng Zhou
Nov 11, 2019·Cells·Alicja M GruszkaMyriam Alcalay
Sep 28, 2018·Molecular Cancer Research : MCR·Molly R RyanKaren S Anderson
Mar 16, 2021·Critical Reviews in Oncology/hematology·Ana Carolina B da C RodriguesDaniel P Bezerra
Jul 3, 2021·International Journal of Molecular Sciences·Vincent KuekLaurence C Cheung
Aug 11, 2021·Journal of Hematology & Oncology·Seyed Esmaeil AhmadiMajid Safa
Aug 13, 2021·Frontiers in Oncology·Giuliana CataraDaniela Spano
Aug 28, 2021·International Journal of Molecular Sciences·Michael LatourElmar Nurmemmedov
Sep 17, 2021·Haematologica·Felice PepeRamiro Garzon

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