Oxidative stress in normal hematopoietic stem cells and leukemia

Abstract

Leukemia is developed following the abnormal proliferation of immature hematopoietic cells in the blood when hematopoietic stem cells lose the ability to turn into mature cells at different stages of maturation and differentiation. Leukemia initiating cells are specifically dependent upon the suppression of oxidative stress in the hypoglycemic bone marrow (BM) environment to be able to start their activities. Relevant literature was identified by a PubMed search (2000-2017) of English-language literature using the terms 'oxidative stress,' 'reactive oxygen species,' 'hematopoietic stem cell,' and 'leukemia.' The generation and degradation of free radicals is a main component of the metabolism in aerobic organisms. A certain level of ROS is required for proper cellular function, but values outside this range will result in oxidative stress (OS). Long-term overactivity of reactive oxygen species (ROS) has harmful effects on the function of cells and their vital macromolecules, including the transformation of proteins into autoantigens and increased degradation of protein/DNA, which eventually leads to the change in pathways involved in the development of cancer and several other disorders. According to the metabolic disorders of cancer, the relationship between OS changes, the viability of cancer cells, and their response to chemotherapeutic agents affecting this pathway are undeniable. Recently, studies have been conducted to determine the effect of herbal agents and cancer chemotherapy drugs on oxidative stress pathways. By emphasizing the role of oxidative stress on stem cells in the incidence of leukemia, this paper attempts to state and summarize this subject.

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side

“…BCR-ABL is probably one of the best examples of leukaemia-driving oncogenes; the expression of the chimeric BCR-ABL tyrosine kinase is sufficient for cell transformation in CML [ 114 ]. Several reports support the idea that BCR-ABL is able to induce ROS production from different sources, including mitochondria [ 115 ], the upregulation of NADPH oxidase activity [ 116 ] by increasing p47 Phox expression [ 117 ] and an enhanced glucose metabolism [ 118 ]. It seems that the increased ROS production would be important for cell growth and transformation.…”

Peperomin E and its orally bioavailable analog induce oxidative stress-mediated apoptosis of acute myeloid leukemia progenitor cells by targeting thioredoxin reductase

“…It was reported that these cells are more sensitive to increases in ROS levels than the normal bone marrow cells. Therefore, increased ROS production or inhibition of the cellular antioxidant systems is increasingly considered as a therapeutic strategy to target the APCs [ 12 , 14 ]. In this study, we discovered that pretreatment of KG-1a CD34 + cells with the free radical scavenger NAC completely abrogated the DMAPE (or PepE)-mediated apoptosis, indicating that the apoptosis-inducing ability of DMAPE (or PepE) is attributed to its capability of promoting ROS production in APCs.…”

“…The unique features that render CD34 + AML cells as a potential risk factor of hematological malignancies are still under debate. Recent studies suggested that the aberrant regulation of signaling pathways such as ROS, NF-κB, Wnt/β-catenin, or Hedgehog pathway is critical to the pathogenesis of CD34 + AML cells [ [11] , [12] , [13] , [14] , [15] , [16] , [17] ]. The recovery of these signaling pathways could be used for the elimination of CD34 + AML cells.…”

Oxidative resistance of leukemic stem cells and oxidative damage to hematopoietic stem cells under pro-oxidative therapy

“…In terms of the metabolism of HSCs, many regulatory mechanisms, including high antioxidant defense and a diversity of regulatory molecules, such as P53, FOXO3, Akt, MAPK, hypoxia inducible factor 1 (HIF-1) and ataxia telangiectasia mutated (ATM), are involved in maintaining the low ROS level of HSCs to protect HSCs from oxidative stress-induced injury [9][10][11][12][13] . Bone marrow stromal cells (BMSCs) residing in the HSC niche also has a vital role in maintaining the redox homeostasis of HSCs, and ROS in HSCs can be transferred to BMSCs, maintaining a low ROS level 14 .…”

“…According to the literature, among various types of leukemia cells, including AML, chronic myeloid leukemia (CML) and promyelocytic leukemia cells, an increase in NOX activity is observed, indicating that NOX's constitutive activation is a very important source of intracellular ROS for LSCs [43][44][45] . Moreover, activated FMS-like tyrosine kinase and oncogenes such as BCR/ABL, cellular-myelocytomatosis viral oncogene and Ras are all closely related to changes in redox homeostasis in leukemic cells and increased ROS levels 9,46,47 . It has been found that antioxidant defense is decreased in different types of leukemia [48][49][50][51] , indicating that an imbalance between the oxidative and antioxidative systems may be one of the reasons for increased ROS levels in leukemic cells.…”