| First Author | Scheller M | Year | 2013 |
| Journal | J Exp Med | Volume | 210 |
| Issue | 11 | Pages | 2239-56 |
| PubMed ID | 24101380 | Mgi Jnum | J:204584 |
| Mgi Id | MGI:5532856 | Doi | 10.1084/jem.20130706 |
| Citation | Scheller M, et al. (2013) Cross talk between Wnt/beta-catenin and Irf8 in leukemia progression and drug resistance. J Exp Med 210(11):2239-56 |
| abstractText | 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. |
