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Review
. 2008 Nov;10(11):1909-21.
doi: 10.1089/ars.2008.2129.

Oxidative stress in Fanconi anemia hematopoiesis and disease progression

Wei Du  1 , Zsuzsanna Adam, Reena Rani, Xiaoling Zhang, Qishen Pang
Affiliations
Review

Oxidative stress in Fanconi anemia hematopoiesis and disease progression

Wei Du et al. Antioxid Redox Signal. 2008 Nov.

Abstract

Patients with the genomic instability syndrome Fanconi anemia (FA) commonly develop progressive bone marrow failure and have a high risk of cancer. The prominent role of the FA protein family involves DNA damage response and/or repair. Oxidative stress, defined as an imbalance between the production of reactive oxygen species and antioxidant defense, is considered to be an important pathogenic factor in leukemia-prone bone marrow diseases such as FA. Cellular responses inducing resistance to oxidative stress are important for cellular survival, organism lifespan, and cancer prevention, but until recently, mammalian factors regulating resistance to oxidative stress have not been well characterized. Significant evidence supports excessive apoptosis of hematopoietic stem/progenitor cells, induced by stresses, most significantly oxidative stress, as a critical factor in the pathogenesis of bone marrow failure and leukemia progression in FA. In this brief review, we discuss the functional link between FA proteins and oxidative DNA damage response/repair, with emphasis on the implication of oxidative stress in the pathophysiology and abnormal hematopoiesis in FA.

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Figures

FIG. 1.
FIG. 1.
Function of the FA pathway. Eight FA proteins form a nuclear complex, which acts as ubiquitin ligase. In response to DNA damage or replication stress, it monoubiquitinates two other FA proteins, FANCD2 and FANCI, which then recruit other downstream FA proteins FANCD1, FANCJ, and FANCN to damaged DNA and influence DNA replication, cell-cycle control, and DNA repair processes
FIG. 2.
FIG. 2.
Consequence of FA defects. Mutations in any of the 13 genes lead to the FA phenotype such as developmental abnormalities, bone marrow failure, and cancer in FA patients
FIG. 3.
FIG. 3.
A model of FA disease progression. FA HSC/P cells are highly susceptible to stress-induced apoptosis, which may lead to HSC depletion and bone marrow failure. The combination of apoptosis and genomic instability provides recrudescent selective sweeps that purge hematopoietic tissues of all but the selected or adapted neoplastic stem cells
FIG. 4.
FIG. 4.
Normal hematopoiesis. Long-term hematopoietic stem cells (LT-HSCs) maintain life-long hematopoiesis in the bone marrow (BM) via their ability to self-renew and to differentiate into all blood lineages. During differentiation, LT-HSCs transit through short-term (ST)–HSCs and committed progenitor stages (characterized by restricted lineage potential and reduced self-renewal capacity) before differentiating into mature myeloid, erythroid, or lymphoid lineages
FIG. 5.
FIG. 5.
The effects of oxidative stress on HSC function. (A) Wild-type (WT) hematopoiesis, in which FA proteins regulate antioxidant response in HSC/P cells. The WT cells then recover from oxidative damage, survive, and proliferate normally. (B) Loss of FA function in HSC/P cells results in an increase in ROS, which ultimately results in increased accumulation of DNA damage and apoptotic death. (C) Reversal of this detrimental effect on HSC/P cells by administration of exogenous antioxidant, such as N-acetyl-L-cysteine (NAC) to the Fancc−/− mice, most likely due to the decrease in ROS
FIG. 6.
FIG. 6.
Manipulation of p53 signaling alters H2O2-induced cell-cycle checkpoint in Fanca −/− bone marrow cells. Note that Fanca−/− cells expressing the p53 inhibitor (p53DD) evade from H2O2-induced G2/M arrest but suffer apoptosis; whereas forced activation of p53 by Nutlin-3a does not induce G2/M arrest in Fanca−/− cells with a functional p53, as evidenced by induction of G0/G1 arrest
FIG. 7.
FIG. 7.
The difference in redox status may result in different levels of p53 activation in WT and FA cells. In WT cells, ROS attach chromosomal DNA and generate oxidative DNA damage, mainly in the form of 8-oxo-deoxyguanosine (8-oxo-dG). The damage can induce the activation of p53 by phosphorylation (for example, phospho-p53 at Ser20–p53Ser20), leading to the repair of the oxidative DNA damage. Loss of FA function leads to increased level of ROS or reduced repair of the oxidative DNA damage. Consequently, FA cells accumulate higher level of oxidative DNA damage, leading higher level of p53 activation
FIG. 8.
FIG. 8.
The pro-inflammatory cytokine TNF-α and its potential role in FA pathophysiology. Overproduced TNF-α plays role in not only pro-apoptotic signal suppressing FA hematopoietic progenitor activity, but also promoting leukemic transformation of FA hematopoietic stem/progenitor cells, which lead to typical phenotype of FA patients
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