title: Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications.
abstract: Neoplastic expansion of myeloid cells is associated with specific genetic changes that lead to chronic activation of signaling pathways, as well as altered metabolism. It has become increasingly evident that transformation relies on the interdependency of both events. Among the various genetic changes, the oncogenic BCR-ABL tyrosine kinase in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) has been a focus of extensive research. Transformation by this oncogene is associated with elevated levels of intracellular reactive oxygen species (ROS). ROS have been implicated in processes that promote viability, cell growth, and regulation of other biological functions such as migration of cells or gene expression. Currently, the BCR-ABL inhibitor imatinib mesylate (Gleevec) is being used as a first-line therapy for the treatment of CML. However, BCR-ABL transformation is associated with genomic instability, and disease progression or resistance to imatinib can occur. Imatinib resistance is not known to cause or significantly alter signaling requirements in transformed cells. Elevated ROS are crucial for transformation, making them an ideal additional target for therapeutic intervention. The underlying mechanisms leading to elevated oxidative stress are reviewed, and signaling mechanisms that may serve as novel targeted approaches to overcome ROS-dependent cell growth are discussed.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Margret S
authors.initials: MS
authors.lastname: Rodrigues
authors.forename: Mamatha M
authors.initials: MM
authors.lastname: Reddy
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia; D002471:Cell Transformation, Neoplastic; D016503:Drug Delivery Systems; D004734:Energy Metabolism; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D022423:Myeloid Cells / Q000201:enzymology / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D015513:Oncogene Proteins / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D005947:Glucose