The role of protein phosphorylation in therapy resistance and disease progression in chronic myelogenous leukemia.

This review focuses on the central role that protein phosphorylation plays in the pathogenesis of chronic myelogenous leukemia (CML). It will cover the signaling pathways that are dysregulated by the oncogenic tyrosine kinase, BCR-ABL1, which both defines and drives the disease, and the barriers to disease control. These will include the mechanisms that underlie drug resistance, as well as the features of CML that prevent its cure by tyrosine kinase inhibitors. In the second section, we will cover the proteins and pathways that lead to the transformation of early chronic-phase CML to the more advanced blast phase of the disease. Here, we will outline the key pathophysiologic differences between the chronic and the blast phase, the mechanisms that contribute to these differences, and how these might be therapeutically targeted in patients. In the final section, we will summarize the major lessons learnt from the CML clinic. We will focus on how these observations have impacted our understanding of the therapeutic potential of modulating protein phosphorylation in human diseases and areas in which future research in CML pathophysiology may be important.