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

• Published in: Blood Vol. 122; no. 19; pp. 3322 - 3330
• Main Authors: Hole, Paul S., Zabkiewicz, Joanna, Munje, Chinmay, Newton, Zarabeth, Pearn, Lorna, White, Paul, Marquez, Nuria, Hills, Robert K., Burnett, Alan K., Tonks, Alex, Darley, Richard L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-11-2013
• Subjects: Antigens, CD34 - genetics; Antigens, CD34 - metabolism; Apoptosis; Case-Control Studies; Cell Proliferation; Gene Expression Regulation, Leukemic; Glutathione - metabolism; Humans; Hydrogen Peroxide - metabolism; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Oxidative Stress; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Primary Cell Culture; Reactive Oxygen Species - metabolism; Signal Transduction
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-04-491944

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.
•More than 60% of primary AML blasts constitutively produce high levels of NOX-derived reactive oxygen species (ROS), which drives AML proliferation.•High ROS AMLs show depleted antioxidant defenses but evade the oxidative stress response through suppression of p38MAPK signaling.