Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities

Abstract

Acute lymphoblastic leukemia (ALL) is a hematological malignancy originating from B- or T-lymphoid progenitor cells. Recent studies have shown that redox dysregulation caused by overproduction of reactive oxygen species (ROS) has an important role in the development and progression of leukemia. The application of pro-oxidant therapy, which targets redox dysregulation, has achieved satisfactory results in alleviating the conditions of and improving the survival rate for patients with ALL. However, drug resistance and side effects are two major challenges that must be addressed in pro-oxidant therapy. Oxidative stress can activate a variety of antioxidant mechanisms to help leukemia cells escape the damage caused by pro-oxidant drugs and develop drug resistance. Hematopoietic stem cells (HSCs) are extremely sensitive to oxidative stress due to their low levels of differentiation, and the use of pro-oxidant drugs inevitably causes damage to HSCs and may even cause severe bone marrow suppression. In this article, we reviewed research progress regarding the generation and regulation of ROS in normal HSCs and ALL cells as well as the impact of ROS on the biological behavior and fate of cells. An in-depth understanding of the regulatory mechanisms of redox homeostasis in normal and malignant HSCs is conducive to the formulation of rational targeted treatment plans to effectively reduce oxidative damage to normal HSCs while eradicating ALL cells.

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

“…ROS levels may influence signaling pathways that are key to control the balance between quiescence and proliferation of HSC. Activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways is required for HSC proliferation ( 30 ); these signaling pathways can be redox regulated and simultaneously contribute to ROS production. AKT behaves as coordinator of a number of different signaling pathways, and it is a crucial regulator of HSC homeostasis.…”

Targeting Redox Regulation as a Therapeutic Opportunity against Acute Leukemia: Pro-Oxidant Strategy or Antioxidant Approach?

“…These compounds can perform their therapeutic action by stimulating ROS generation. However, several experiments show that a multiplicity of different substances could alter the oxidative regulation to increase the destruction of clonal cells, including histone deacetylase inhibitors (HDACIs), proteasome inhibitors, heme oxygenase-1 inhibitors such as protoporphyrin, and thioredoxin inhibitors [ 106 ]. Furthermore, thiopurines, which are the most relevant drugs employed in the maintenance therapy for ALL, may increase OS and this might be the system implicated in thiopurine-driven cytotoxicity [ 107 , 108 ].…”

Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: Reducing Radicals to Refine Responses

“…Mammalian cells have evolved complex antioxidant systems that can counter the toxic effects of elevated H 2 O 2 and hence cellular oxidative stress (Figure 1) (reviewed in [60]). These antioxidant systems are mainly divided into enzymatic and non-enzymatic processes that are crucial in maintaining a balance between oxidative stress and essential redox signalling, often referred to as redox homeostasis.…”

“…In addition to HIF signalling, ataxia-telangiectasia mutation (ATM), forkhead box class O transcription factor (FoxO), Akt, and mTOR signalling pathways are also crucial in the regulation of redox homeostasis and HSCs quiescence (reviewed in [60]). FoxOs are transcriptional factors that act downstream to PTEN/PI3K/Akt pathway, considered essential for the self-renewal capacity of HSCs.…”

“…NF-κB proteins are a family of transcription factors that regulate immune responses to pathogens, inflammation, promote growth and proliferation, and cell development [178]. Indeed, NF-κB transcription factors are responsible for the expression of the ROS producing NADPH oxidase enzymes [179] (discussed in Sections 3, 5.2, 5.7, 5.8 and 7.2) but can also upregulate the expression of antioxidants (reviewed in [60]). Not only does NF-κB activity increase NADPH oxidase expression and hence ROS production, but ROS regulates the transcriptional activity of NF-κB through degradation of the NF-κB inhibitory protein IκB, promoting nuclear translocation and transcription of κB genes, creating both a feed-forward and positive feedback loop [180,181].…”