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

Marina Scheller; Jörg Schönheit; Karin Zimmermann; Ulf Leser; Frank Rosenbauer; Achim Leutz

doi:10.1084/jem.20130706

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

J Exp Med. 2013 Oct 21;210(11):2239-56. doi: 10.1084/jem.20130706. Epub 2013 Oct 7.

Authors

Marina Scheller¹, Jörg Schönheit, Karin Zimmermann, Ulf Leser, Frank Rosenbauer, Achim Leutz

Affiliation

¹ Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.

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/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive β-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and Imatinib resistance. Interestingly, activated β-catenin enhances a preexisting Irf8-deficient gene signature, identifying β-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 β-catenin-driven leukemia and imply both factors as targets in combinatorial therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzamides / pharmacology
Blast Crisis / genetics
Blast Crisis / pathology
Disease Progression*
Drug Resistance, Neoplasm*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Hematopoietic Stem Cells / drug effects
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / pathology
Humans
Imatinib Mesylate
Immunophenotyping
Interferon Regulatory Factors / deficiency
Interferon Regulatory Factors / metabolism*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
Mice
Myeloid Cells / drug effects
Myeloid Cells / metabolism
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Piperazines / pharmacology
Pyrimidines / pharmacology
Side-Population Cells / drug effects
Side-Population Cells / metabolism
Side-Population Cells / pathology
Wnt Signaling Pathway*

Substances

Benzamides
Interferon Regulatory Factors
Piperazines
Pyrimidines
interferon regulatory factor-8
Imatinib Mesylate