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Review
. 2008 Nov;10(11):1923-40.
doi: 10.1089/ars.2008.2142.

Oxidative stress in the regulation of normal and neoplastic hematopoiesis

Saghi Ghaffari  1
Affiliations
Review

Oxidative stress in the regulation of normal and neoplastic hematopoiesis

Saghi Ghaffari. Antioxid Redox Signal. 2008 Nov.

Abstract

Recent evidence suggests that oxidative stress contributes significantly to the regulation of hematopoietic cell homeostasis. In particular, red blood cells and hematopoietic stem cells are highly sensitive to deregulated accumulation of reactive oxygen species (ROS). Unchecked ROS accumulation often leads to hemolysis, that is, to destruction and shortened life span of red blood cells. In addition, the process of erythroid cell formation is sensitive to ROS accumulation. Similarly, ROS buildup in hematopoietic stem cells compromises their function as a result of potential damage to their DNA leading to loss of quiescence and alterations of hematopoietic stem cell cycling. These abnormalities may lead to accelerated aging of hematopoietic stem cells or to hematopoietic malignancies.

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Figures

FIG. 1.
FIG. 1.
Reactive oxygen species. Cells generate aerobic energy by reducing molecular oxygen (O2) to water. During the metabolism of oxygen, superoxide (−O2) is occasionally formed. Superoxide is rapidly dismutated to hydrogen peroxide (H2O2), which is converted by glutathione peroxidase or catalase to water. MPD (myeloperoxidase) converts H2O2 in neutrophils to hypochlorous acid (HOCl), a strong oxidant that acts as a bactericidal agent in phagocytic cells. During a Fenton reaction, H2O2 is converted in a spontaneous reaction catalyzed by Fe2+ to the highly reactive hydroxyl radical ·OH.
FIG. 2.
FIG. 2.
Schematic of erythroid cell differentiation. The most mature erythroid progenitor (colony-forming unit–erythroid cell, CFU-E) expresses the highest levels of EpoR during erythropoiesis. CFU-Es divide to produce erythroid precursor cells, and EpoR expression is downregulated during this process on erythroid precursors. Erythroid cells accumulate hemoglobin as they mature. It is noteworthy that whereas erythroid cells generated from the first divisions of CFU-E require Epo, Epo becomes dispensible for the maturation of subsequent erythroid cells.
FIG. 3.
FIG. 3.
FoxO role in the regulation of oxidative stress is evolutionarily conserved. FoxO are the mammalian homologues of DAF-16 in Caenorhabditis elegans. These transcription factors are regulated by the highly conserved IGF-1 (Insulin)/PI3-kinase/AKT signaling pathway that suppress the activity of FoxO. Activation of DAF-16 enhances the worm's life span in part through resistance to oxidative stress. In mammals, active FoxO plays key roles in the regulation of transcription of several antioxidant enzymes, as well as the cell cycle, DNA repair, apoptosis, and cell-differentiation proteins.
FIG. 4.
FIG. 4.
Model for the regulation of FoxO3 in erythroid cells. As postprogenitor erythroid precursors differentiate, hemoglobin is synthesized, and the expression of EpoR is decreased. AKT is active in erythroid progenitors, where it inhibits FoxO3. In erythroid precursors, downregulation of AKT signaling as a result of reduced expression of EpoR, coupled with accumulation of hemoglobin, produces ROS and activates nuclear localization of FoxO3. FoxO3 nuclear activity may coordinate the cell cycle and maturation by modulating ROS accumulation in erythroid precursor cells.
FIG. 5.
FIG. 5.
FoxO3 regulation of ROS coordinates the erythroid cell cycle and differentiation and determines the rate of erythroid cell maturation. (A) Nuclear FoxO3 activity in erythroid precursors represses ROS under normal conditions to coordinate the erythroid cell cycle and maturation. (B) In the absence of FoxO3, ROS accumulate in erythroid precursors, leading to the activation of p53/p21CIP1/WAF1/Sdi1, resulting in arrest of precursors in G1, reduced mature cells, and overproduction of precursors as a result of progenitor activity.
FIG. 6.
FIG. 6.
ATM/FoxO3/p53 axis of ROS control in hematopoietic stem cells. ROS activate ATM, FoxO3, p53 tumor suppressors, and each independently or in a cascade induces the expression of antioxidant enzymes to repress ROS.
FIG. 7.
FIG. 7.
ROS activation of tumor suppressors in hematopoietic stem cells leads to senescence or genomic instability. Accumulation of ROS in hematopoietic stem cells activates tumor-suppressor pathways, presumably in response to damage, and in particular to DNA damage. This activation leads to senescence of hematopoietic stem cells. Cells that escape senescence may accumulate, increasing damage and perhaps mutations that undermine their genomic stability and provide them with a proliferative advantage leading to their clonal expansion.
FIG. 8.
FIG. 8.
Modeling the function of FoxO3 in hematopoietic stem versus progenitor cells. The function of FoxO3 may be distinct in hematopoietic stem cells versus progenitor cells. In hematopoietic stem cells, FoxO3 is constitutively active to promote antioxidant resistance and quiescence. In hematopoietic progenitor cells that are subject to cytokines, ROS may play an active role in the regulation of cytokine-receptor signaling. In hematopoietic progenitors, FoxO3 is suppressed while ROS are under a certain threshold, above which, FoxO3 is activated to induce apoptosis. This model provides an intrinsic ROS-mediated dynamic balance between the degree of proliferation and survival of hematopoietic progenitors. Tight regulation of ROS via FoxO3 thwarts unlimited generation of hematopoietic progenitors.
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