**7. Functional interaction between the FA proteins and other oxidative stress response pathways**

Recent findings of a reduction of the HSC pool and a deficient repopulating capacity in Foxo3a knockout animals (Miyamoto *et al.,* 2007) indicate that FOXO3a plays essential regulatory roles in HSC maintenance through a mechanism of regulating ROS. This is consistent with our recent finding that FANCD2 forms complex with FOXO3a in response to oxidative stress (Li *et al.,* 2010). In addition, we observed several hematopoietic defects in FA mice deficient for Foxo3a (unpublished data). These results suggest that the FA proteins functionally interplay with other oxidative stress response pathways. Indeed, our preliminary results with primary BM cells from FA-A patients show that certain genes functioning in anti-oxidant defense and ROS metabolism fail to respond to oxidative stress (unpublished data). This suggests that one critical function of FA proteins under oxidative stress is to safeguard the expression of these anti-oxidant defense genes through DNA damage repair or gene promoter protection. While these observations indicate that the FA pathway functionally interacts with other cellular oxidative stress response pathways, the molecular mechanisms by which FA proteins function to modulate physiologic oxidative stress remain to be elucidated. Further investigation into the roles of FA proteins in oxidative DNA-damage response and repair, and the functional relationship between inflammatory ROS and genomic instability during FA leukemogenesis not only will advance our understanding of the function of FA proteins in hematopoiesis but also may suggest new targets for therapeutic prevention and treatment of BM failure and cancer progression of the disease.
