Gene expression changes associated with progression of Irf8–/– CML-like disease into blast crisis after β-catenin activation

ABSTRACT: Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics, we observed that compound constitutive activation of β-catenin and deletion of Irf8 results in progression of CML-like disease into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and accumulation of Imatinib-resistant LICs in GMP-like populations. We found that progression of the disease is tightly connected to the magnitude of gene expression and that activated β-catenin enhances a pre-existing Irf8-deficient gene signature that was defined as a “progression specific signature” (PSS). We identified β-catenin as an amplifier of disease progression and as a critical step 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. We used microarrays to identify the gene expression signature in GMPs underlying CML-like disease progression and identified distinct classes of up- and down-regulated genes during this process defined as a “progression specific signature (PSS)”.

ORGANISM(S): Mus musculus

PROVIDER: GSE49054 | GEO | 2013/09/26

SECONDARY ACCESSION(S): PRJNA213468

REPOSITORIES: GEO