| First Author | Rodríguez A | Year | 2021 |
| Journal | Exp Hematol | Volume | 93 |
| Pages | 70-84.e4 | PubMed ID | 33166613 |
| Mgi Jnum | J:322057 | Mgi Id | MGI:6750970 |
| Doi | 10.1016/j.exphem.2020.11.002 | Citation | Rodriguez A, et al. (2021) Inhibition of TGFbeta1 and TGFbeta3 promotes hematopoiesis in Fanconi anemia. Exp Hematol 93:70-84.e4 |
| abstractText | Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor beta (TGFbeta) pathway, regulated by the TGFbeta1, TGFbeta2, and TGFbeta3 ligands. Accordingly, the TGFbeta pathway is an attractive therapeutic target for FA. While inhibition of TGFbeta1 and TGFbeta3 promotes blood cell expansion, inhibition of TGFbeta2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGFbeta1- and TGFbeta3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA. |
