FA is a genomic instability syndrome that is uniquely susceptible to physiologic oxidative stress, as patients accumulate abnormal levels of inflammatory ROS generated by overproduced TNF-. In FA inflammation-associated leukemogenesis, several non-mutually exclusive mechanisms may be involved, including defective DNA damage repair, impaired DNA damage response, and increased genomic instability.
We hypothesize that increased ROS accumulation and vulnerability of the FA chromosomal DNA to oxidative damage would provide a genetic mechanism for FA genomic instability. We will employ two FA preleukemic models (FA patients at the MDS stage and the inflammation-induced Fancc-/- mouse preleukemic cells) to investigate the cellular mechanisms responsible for leukemic transformation in FA HSCs, with focus on 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.
By demonstrating the link between inflammation and genomic instability, our study will challenge the current view of FA genomic instability being restricted to cross linker-induced DNA damage, with mechanistic implications for the health consequences of chronic inflammation particularly in the context of leukemogenesis.