Tumor Necrosis Factor-Mediated Inflammation Exacerbates Genomic Instability and Promotes Leukemia Development.

A correlation has been shown between elevated circulating pro-inflammatory cytokines and anemia in patients with leukemia-related diseases but direct evidence for the mechanistic link between inflammation and leukemia is lacking. We have investigated the role of the pro-inflammatory cytokine tumor necrosis factor a (TNF-a) in leukemic development using the disease model of Fanconi anemia, a genetic disorder clinically characterized by congenital anomalies, progressive bone marrow failure, and a high risk of developing leukemia and other cancers. We demonstrate that long-term TNF-a exposure of Fanconi bone marrow progenitors enhances inflammatory response, promotes clonal proliferation, and ultimately leads to leukemia development. NF-kB activation is required for TNF-a-promoted progenitor growth and early stage of leukemia development but is dispensable for the maintenance of leukemic transformation. Pharmacological elimination of TNF-a-induced reactive oxygen species reduces inflammation and delays leukemia development, suggesting that oxidative damage may serve as a link between inflammation and leukemia. In addition, TNF-a-promoted leukemic cells show persistent DNA damage response and increased genomic instability. Furthermore, correction of Fanconi genetic deficiency prevents clonal progenitor proliferation and leukemic transformation by eliminating oxidative DNA damage. Thus, inflammation can exacerbate genomic instability and contribute to leukemia development. This may explain, at least in part, why cells with genomic instability have high predisposition to cancer. Our study underscores therapeutic value of anti-oxidants and anti-inflammation towards tumorigenesis.