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Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling

Hole, Paul Spencer, Zabkiewicz, Joanna, Munje, Chinmay, Newton, Zarabeth, Pearn, Lorna, White, Paul Charles, Marquez, Nuria, Hills, Robert Kerrin, Burnett, Alan Kenneth, Tonks, Alex and Darley, Richard Lawrence 2013. Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling. Blood 122 (19) , pp. 3322-3330. 10.1182/blood-2013-04-491944

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Abstract

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 (mean >10-fold) in >60% 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 p38MAPK. Consistent with this, we observed that p38MAPK 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 15 Oct 2018 03:39
URI: http://orca.cf.ac.uk/id/eprint/52860

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