Context-specific effects of NOX4 inactivation in acute myeloid leukemia (AML)

Abstract

Purpose Oxidative stress has been linked to initiation and progression of cancer and recent studies have indicated a potential translational role regarding modulation of ROS in various cancers, including acute myeloid leukemia (AML). Detailed understanding of the complex machinery regulating ROS including its producer elements in cancer is required to define potential translational therapeutic use. Based on previous studies in acute myeloid leukemia (AML) models, we considered NADPH oxidase (NOX) family members, specifically NOX4 as a potential target in AML. Methods Pharmacologic inhibition and genetic inactivation of NOX4 in murine and human models of AML were used to understand its functional role. For genetic inactivation, CRISPR-Cas9 technology was used in human AML cell lines in vitro and genetically engineered knockout mice for Nox4 were used for deletion of Nox4 in hematopoietic cells via Mx1-Cre recombinase activation. Results Pharmacologic NOX inhibitors and CRISPR-Cas9-mediated inactivation of NOX4 and p22-phox (an essential NOX component) decreased proliferative capacity and cell competition in FLT3-ITD-positive human AML cells. In contrast, conditional deletion of Nox4 enhanced the myeloproliferative phenotype of an FLT3-ITD induced knock-in mouse model. Finally, Nox4 inactivation in normal hematopoietic stem and progenitor cells (HSPCs) caused a minor reduction in HSC numbers and reconstitution capacity. Conclusion The role of NOX4 in myeloid malignancies appears highly context-dependent and its inactivation results in either enhancing or inhibitory effects. Therefore, targeting NOX4 in FLT3-ITD positive myeloid malignancies requires additional pre-clinical assessment.

Role of reactive oxygen species in myelodysplastic syndromes

“…Hole et al [87] reported that the constitutive activation of NOXs caused the generation of extracellular ROS to be significantly augmented in more than 60% of patients with AML and that the increased ROS prompted the proliferation of AML cells, as well as normal CD34 + cells, to a lesser extent. Demircan et al [88] analyzed the important role of the NOX family member NOX4 in AML using human AML cells and mouse models. They revealed that the proliferation ability and cell competition were reduced in fmslike receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive human AML cells upon inhibition of the enzymatic activity of NOX4 and p22 phox .…”

“…Demircan et al. [ 88 ] analyzed the important role of the NOX family member NOX4 in AML using human AML cells and mouse models. They revealed that the proliferation ability and cell competition were reduced in fms-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive human AML cells upon inhibition of the enzymatic activity of NOX4 and p22 phox .…”

Predominant factors influencing reactive oxygen species in cancer stem cells

“…Monocytes and macrophages generate high levels of superoxides through NOX as a part of their microbicidal mechanisms. Different members of the NOX family have been reported to be associated with the development of various cancers such as acute myeloid leukemia, 7 gastric cancer, 8 and hepatocellular carcinoma 9 . The peroxisome is a dynamic organelle involved in various metabolic processes such as fatty acid α ‐ and β oxidation, amino acid catabolism, and the glyoxylate cycle.…”

Oxidative stress is two‐sided in the treatment of acute myeloid leukemia

“…The two primary sources of ROS in tumor cells are the mitochondrial respiratory chain and NOX 17,18 . The NOX protein family consists of seven enzyme complexes, including NOX1‐5 and two related dual oxidases (DUOX1‐2) 19 . We review recent studies on oxidative stress and redox homeostasis in AML, with the urgency to find new therapies to target relapsed/chemoresistant AML cells susceptible to the latest drugs.…”