The presence of a BCR-ABL1 fusion gene is necessary for the pathogenesis of chronic myeloid leukemia (CML) through t(9;22)(q34;q11) translocation. Imatinib, an ABL tyrosine kinase inhibitor, is dramatically effective in CML patients; however, 30% of CML patients will need further treatment due to progression of CML to blast crisis (BC). Aberrant high expression of ecotropic viral integration site 1 (EVI1) is frequently observed in CML during myeloid-BC as a potent driver with a CML stem cell signature; however, the precise molecular mechanism of EVI1 transcriptional regulation during CML progression is poorly defined. Here, we demonstrate the transcriptional activity of EVI1 is dependent on activation of lymphoid enhancer-binding factor 1 (LEF1)/beta-catenin complex by BCR-ABL with loss of p53 function during CML-BC. The activation of beta-catenin is partly dependent on BCR-ABL expression through enhanced GSK3 beta phosphorylation, and EVI1 expression is directly enhanced by the LEF1/beta-catenin complex bound to the EVI1 promoter region. Moreover, the loss of p53 expression is inversely correlated with high expression of EVIL in CML leukemia cells with an aggressive phase of CML, and a portion of the activation mechanism of EVIL expression is dependent on beta-catenin activation through GSK3 beta phosphorylation by loss of p53. Therefore, we found that the EVI1 activation in CML-BC is dependent on LEF1 beta-catenin activation by BCR-ABL expression with loss of p53 function, representing a novel selective therapeutic approach targeting myeloid blast crisis progression. (C) 2016 Elsevier Inc. All rights reserved.