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Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance

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Item Type:Article
Title:Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance
Creators Name:Scheller, M. and Schönheit, J. and Zimmermann, K. and Leser, U. and Rosenbauer, F. and Leutz, A.
Abstract:Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/{beta}-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of {beta}-catenin results in up-regulation of Irf8, which in turn limits oncogenic {beta}-catenin functions. Self-renewal and myeloproliferation become dependent on {beta}-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive {beta}-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and Imatinib resistance. Interestingly, activated {beta}-catenin enhances a preexisting Irf8-deficient gene signature, identifying {beta}-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for {beta}-catenin-driven leukemia and imply both factors as targets in combinatorial therapy.
Keywords:BCR-ABL Positive Chronic Myelogenous Leukemia, Benzamides, Blast Crisis, Disease Progression, Gene Expression Profiling, Hematopoietic Stem Cells, Immunophenotyping, Interferon Regulatory Factors, Myeloid Cells, Neoplasm Drug Resistance, Neoplastic Gene Expression Regulation, Neoplastic Stem Cells, Piperazines, Pyrimidines, Side-Population Cells, Wnt Signaling Pathway, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:2239-2256
Date:21 October 2013
Official Publication:https://doi.org/10.1084/jem.20130706
PubMed:View item in PubMed

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