Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

Figure 3

Mechanisms of CML cells resistance to TKI. BCR-ABL dependent mechanisms include (1) duplication or overamplification of the BCR-ABL oncogene that might lead to an elevated ABL kinase activity or (2) BCR-ABL mutations that affect TKI binding. BCR-ABL independent mechanisms deal with complications such as drug concentration (3), sequestration of imatinib in the plasma by the serum protein acid glycoprotein (AGP) or drug binding (4), increased expression of the P-glycoprotein (Pgp) efflux pump or drug efflux (5), and reduced expression of the organic cation transporter hOCT1 or drug influx (6). Other mechanisms that play a role in TKI resistance and CML progression include activation of alternative signaling pathways downstream of BCR-ABL (7).