| First Author | Zhang H | Year | 2016 |
| Journal | Cell Stem Cell | Volume | 18 |
| Issue | 5 | Pages | 668-81 |
| PubMed ID | 27053300 | Mgi Jnum | J:235076 |
| Mgi Id | MGI:5792756 | Doi | 10.1016/j.stem.2016.03.002 |
| Citation | Zhang H, et al. (2016) TGF-beta Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia. Cell Stem Cell 18(5):668-81 |
| abstractText | 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 from FA 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. |
