title: Evolutionary Dynamics of Chronic Myeloid Leukemia Progression: the Progression-Inhibitory Effect of Imatinib.
abstract: The t(9;22) translocation that causes chronic myeloid leukemia (CML) drives both transformation and the progression process that eventually results in the disease changing to acute leukemia. Constitutively activated Bcr-Abl signaling in CML creates high levels of reactive oxygen species (ROS) that produce 8-oxo-guanine in DNA; this is mutagenic and causes chronic phase (CP) progression to blast phase (BP). We modeled three types of mutations involved in this progression: mutations that result in myeloid progenitor cells proliferating independently of external growth factors; mutations causing failure of myeloid progenitor cells to differentiate; and mutations that enable these cells to survive independently of attachment to marrow stroma. We further modeled tyrosine kinase inhibitors (TKI) as restoring myeloid cell apoptosis and preventing ROS-driven mutagenesis, and mutations that cause TKI resistance. We suggest that the unusually low rate of resistance to TKI arises because these drugs deplete ROS, which in turn decrease mutation rates.
authors.affiliation: Pharmacometrics Ltd, 51 North Road, Whittlesford, Cambridge, CB22 4NZ, UK. rjackson1943@aol.com.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Jackson
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: chronic myeloid leukemia; evolutionary dynamics; genetic instability; imatinib; malignant progression; reactive oxygen species