Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling
| Autor: | Joanna Zabkiewicz, Chinmay Munje, Nuria Marquez, Lorna Pearn, Richard Lawrence Darley, Alan Kenneth Burnett, Alex Tonks, Paul S. Hole, Paul Charles White, Zarabeth Newton, Robert Kerrin Hills |
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| Rok vydání: | 2013 |
| Předmět: |
Mitochondrial ROS
Primary Cell Culture Immunology Clone (cell biology) Antigens CD34 Apoptosis Biology Mitochondrion medicine.disease_cause p38 Mitogen-Activated Protein Kinases Biochemistry chemistry.chemical_compound hemic and lymphatic diseases medicine Humans Cell Proliferation chemistry.chemical_classification Reactive oxygen species Gene Expression Regulation Leukemic Oxidative Stress Pathway NADPH Oxidases Hydrogen Peroxide Cell Biology Hematology Glutathione Cell biology Leukemia Myeloid Acute Oxidative Stress chemistry Case-Control Studies Leukocytes Mononuclear Reactive Oxygen Species Oxidative stress Nicotinamide adenine dinucleotide phosphate Signal Transduction |
| Zdroj: | Blood. 122:3322-3330 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2013-04-491944 |
| Popis: | Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and is known to strongly influence hematopoietic cell function. Here we report that extracellular ROS production is strongly elevated (mean10-fold) in60% of acute myeloid leukemia (AML) patients and that this increase is attributable to constitutive activation of nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction of mitochondrial ROS was rarely observed. Elevated ROS was found to be associated with lowered glutathione levels and depletion of antioxidant defense proteins. We also show for the first time that the levels of ROS generated were able to strongly promote the proliferation of AML cell lines, primary AML blasts, and, to a lesser extent, normal CD34(+) cells, and that the response to ROS is limited by the activation of the oxidative stress pathway mediated though p38(MAPK). Consistent with this, we observed that p38(MAPK) responses were attenuated in patients expressing high levels of ROS. These data show that overproduction of NOX-derived ROS can promote the proliferation of AML blasts and that they also develop mechanisms to suppress the stress signaling that would normally limit this response. Together these adaptations would be predicted to confer a competitive advantage to the leukemic clone. |
| Databáze: | OpenAIRE |
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