| First Author | Dussiot M | Year | 2014 |
| Journal | Nat Med | Volume | 20 |
| Issue | 4 | Pages | 398-407 |
| PubMed ID | 24658077 | Mgi Jnum | J:210302 |
| Mgi Id | MGI:5570442 | Doi | 10.1038/nm.3468 |
| Citation | Dussiot M, et al. (2014) An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med 20(4):398-407 |
| abstractText | The pathophysiology of ineffective erythropoiesis in beta-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of beta-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with beta-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of alpha-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in beta-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in beta-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and alpha-globin precipitation. |
