The present study demonstrated that BM environment induced CML cells resistance to IM through activation of CXCL12/CXCR4/β-catenin/P-gp pathway, while Oroxylin A potentiate the anti-leukemia activity of IM to CML cells by interfering with CXCL12/CXCR4 activation and inhibiting the expression of P-gp in vitro and in vivo. This evidence concerns the gene CXCL12 and chronic myelogenous leukemia, BCR-ABL1 positive.