title: The role of protein phosphorylation in therapy resistance and disease progression in chronic myelogenous leukemia.
abstract: 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.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Wen Chun
authors.initials: WC
authors.lastname: Juan
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D010749:Phosphoprotein Phosphatases