Fanconi Anemia (FA) is an inherited DNA repair disorder characterized by congenital abnormalities, cancer predisposition, and progressive bone marrow failure. FA is caused by biallelic mutations in one of sixteen FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway. Although the precise biochemical functions of the FA/BRCA pathway remain unclear, the pathway promotes homologous recombination (HR) repair. Due to the underlying DNA repair defect, FA cells are hypersensitive to genotoxic DNA crosslinking agents. The mechanism of the bone marrow failure (BMF) in FA remains elusive. Our recent studies suggest that BMF results, at least in part, from increased p53 expression in hematopoietic stem and progenitor cells (HSCPs), leading to progressive cell cycle delay and apoptosis. BMF may also result from the accumulation of DNA damage from the endogenous crosslinking agent, acetaldehyde, and the selective toxicity of this agent to hematopoietic stem cells. Recently, we identified hyperactive TGF? signaling as a mechanism of bone marrow suppression in FA. Disruption of TGF? signaling, through the use of shRNAs, sgRNAs, and small molecule inhibitors confirmed the suppressive role of the pathway on FA cell growth. We hypothesize that an upstream inhibitor of the TGF? pathway (i.e., a monoclonal antibody to TGF? itself) will inhibit this pathway and rescue the function of the HSPCs and FA stromal fibroblasts, resulting in an increased probability of rescuing bone marrow function in FA patients.
The specific aims of this R01 are: 1) To determine whether hyperactivation of the TGF? pathway suppresses growth of primary FA cells and FA cell lines, 2) To determine the mechanism by which TGF? inhibitors promote FA cellular growth and enhanced resistance to crosslinkers, and 3) To determine the mechanism of TGF?-mediated suppression of bone marrow in vivo in mouse models.
Our laboratory has recently determined that a hyperactive TGF? signaling pathway may account, at least in part, for the bone marrow disease and perhaps for the other developmental abnormalities, such as skeletal and limb abnormalities, in Fanconi anemia (FA). Our project will further examine the role of TGF? in the disease progression of FA, with the ultimate goal of developing novel approaches to treating bone marrow failure in FA patients.
