**8. Conclusion**

50 Cancer Prevention – From Mechanisms to Translational Benefits

cytogenetic abnormalities and myeloid malignancies in *Fancc-/-* BM cells (Haneline *et al.,* 1998, 1999, 2003; Li X *et al.,* 2004; Si *et al.,* 2006). While the role of FA proteins in the regulation of TNF--induced ROS production remains to be elucidated, several hypotheses have been proposed, including that FA proteins protect chromosomal DNA from ROS attack or facilitate the repair of oxidative DNA damage, which in turn downstream ROS signaling. It is also possible that FA proteins can regulate the biosynthesis of ROS metabolic molecules, such as glutathione and the expression of antioxidant enzymes (such as glutathione *S*transferases and catalase). However, there is no direct evidence for any of these assumptions so far. Another potential target is the redox-sensitive transcription factor NF-

B, a major player involved in transcription regulating during differentiation and

and promote cancer (Coussens *et al.,* 2002; Fiers *et al.,* 1999; Macdougal *et al.,* 2002). In

environment selects for somatically mutated preleukemic stem cell clones which are apoptosis-resistant and acquire proliferative advantage (Li *et al.,* 2007). Patients with these TNF--resistant BM cells may advance to MDS and AML via a mechanism involving

Fig. 4. The pro-inflammatory cytokines and their potential role in FA pathophysiology. Overproduced pro-inflammatory cytokines (TNF-, IL-6, IL-1 etc.) plays roles in not only pro-apoptotic signal suppressing FA hematopoietic progenitor activity, but also promoting leukemic transformation of FA HSC/P cells, which lead to typical phenotype of FA patients.

addition, chronic exposure of FA BM cells to proinflammatory cytokine TNF-

genomic instability, coupled with inflammation driven by high NF-

B is known to enhance inflammation

creates an

B transcriptional

inflammation (Dhar *et al.,* 2006). The activation of NF-

activity (Fig. 4).

Given other known genomic instability syndromes such as ataxia telangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, and Werner syndrome rarely develop BM failure and leukemia, FA has been considered an excellent disease model for studying oxidative stress response in cancer development. Further investigation into the function of FA proteins in oxidative damage response and repair will help shed new light on the role of FA proteins in the maintenance of normal hematopoiesis under conditions of oxidative stress, and yield valuable information on whether targeting components of FA-related oxidative stress signaling pathways may be therapeutically useful in the prevention and treatment of FA BMF and leukemia. In addition, while FA is a rare disease, understanding functional interaction between FA proteins and other critical oxidative stress signaling pathways provides a unique opportunity to mechanistically comprehend and potentially intervene in these physiologically important processes.
