TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia

Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-beta (TGF-beta) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-beta pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived fromFA mice and FA patients. Inhibition of TGF-beta signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-beta signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA.