title: Reactive oxygen species in BCR-ABL1-expressing cells - relevance to chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells. CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis. Introducing imatinib and other tyrosine kinase inhibitors (TKIs) to CML therapy radically improved its outcome, but TKIs-resistance became an emerging problem. TKI resistance can be associated with even higher ROS production than in TKI-sensitive cells. Therefore, ROS-induced self-mutagenesis of BCR-ABL1 can be crucial for CML progression and TKI resistance and in this way should be taken into account in therapeutic strategies. As a continuous production of ROS by BCR-ABL1 would lead to its self-destruction and death of CML cells, there must be mechanisms controlling this phenomenon. These can be dependent on DNA repair, which is modulated by BCR-ABL1 and can be different in CML stem and progenitor cells. Altogether, the mechanisms of the involvement of BCR-ABL1 in ROS signaling can be engaged in CML progression and TKI-resistance and warrant further study.
authors.affiliation: Department of Maxillofacial Orthopedics and Orthodontics, Medical University of Wroclaw, Wrocław, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Antoszewska-Smith
authors.affiliation: Department of Orthodontics, Medical University of Lodz, Łódź, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pawlowska
authors.affiliation: Department of Molecular Genetics, University of Lodz, Łódź, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Blasiak
mesh_terms: D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D016044:Fusion Proteins, bcr-abl
keywords: DNA damage; DNA repair; cancer stem cells; chronic myeloid leukemia; imatinib resistance; reactive oxygen species