Novel roles of reactive oxygen species in the pathogenesis of acute myeloid leukemia

Abstract

It has become apparent that regulation of ROS is important in cell signaling and homeostasis. Accumulation of ROS triggers oxidative stress in various cell types and contributes to the development, progression, and persistence of cancer. Recent research has demonstrated that redox dysregulation caused by ROS promotes proliferation, differentiation, genomic, and epigenetic alterations; immune evasion; and survival in leukemic cells. ROS act as signaling molecules to regulate redox-sensitive transcriptional factors, enzymes, oncogenes, and other downstream effectors. Thus, a thorough understanding the role of ROS as key mediators in leukemogenesis is likely to provide opportunities for improved pharmacological intervention. In this review, we summarize the recent findings that support a role for ROS in the pathogenesis of AML and outline innovative approaches in the implementation of redox therapies for myeloid malignancies.

Keywords: ROS; cell signaling; leukemogenesis.

Figure 1.. ROS regulation of hematopoiesis via stem cell self-renewal.

HSCs have self-replicating potential that allows them to constantly replenish blood cells. Elevated ROS levels, present in normal hematopoiesis, lead to reduced self-renewal and hematopoiesis. Elevated ROS levels reduce the self-renewal of HSCs and inhibit hematopoiesis. Deletion of specific genes affects HSC integrity by modulating ROS levels. ^−/−, Deficient; RNAi, RNA interference.

Figure 2.. Altered ROS levels stimulate leukemogenesis.

Oxidative stress has been implicated in the pathogenesis of AML. Aberrant ROS signaling triggers damage to nuclear and mitochondrial DNA and compromises DNA repair via increasing a cell's mutation rate and/or promoting and maintaining the oncogenic phenotype as a secondary messenger in intracellular signaling cascades.

Figure 3.. Immune evasion via ROS.

(A) NK cells are potential effectors of innate immunity that are regulated by efficient immunomodulatory and cytotoxic mechanisms that are essential for eliminating AML cells. (B) Elevated ROS levels trigger apoptosis in NK cells, CD4⁺ T cells, and CD8⁺ T cells, whereas AML cells use ROS signaling as a strategy to evade cell-mediated immunity.