An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia.

Abstract

The pathophysiology of ineffective erythropoiesis in β-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 β-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 β-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of α-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 β-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 β-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and α-globin precipitation.

• Authors: Michael Dussiot, Thiago T Maciel, Aurélie Fricot, Céline Chartier, Olivier Negre, Joel Veiga, Damien Grapton, Etienne Paubelle, Emmanuel Payen, Yves Beuzard, Philippe Leboulch, Jean-Antoine Ribeil, Jean-Benoit Arlet, Francine Coté, Geneviève Courtois, Yelena Z Ginzburg, Thomas O Daniel, Rajesh Chopra, Victoria Sung, Olivier Hermine, Ivan C Moura
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 4 Pg. 398-407 (Apr 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 24658077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ACE-011
• Bone Morphogenetic Proteins
• Fas Ligand Protein
• GDF11 protein, human
• Gdf11 protein, mouse
• Growth Differentiation Factors
• Hematinics
• Ligands
• Reactive Oxygen Species
• Recombinant Fusion Proteins
• fas Receptor
• Activin Receptors, Type II
• activin receptor type II-A

Topics

• Activin Receptors, Type II (metabolism)
• Animals
• Apoptosis (physiology)
• Autocrine Communication (physiology)
• Bone Morphogenetic Proteins (antagonists & inhibitors, metabolism)
• Cell Differentiation
• Disease Models, Animal
• Erythroblasts (metabolism)
• Erythropoiesis (drug effects)
• Fas Ligand Protein
• Gene Amplification (physiology)
• Growth Differentiation Factors (antagonists & inhibitors, metabolism)
• Hematinics (pharmacology)
• Ligands
• Mice
• Oxidative Stress (physiology)
• Reactive Oxygen Species
• Recombinant Fusion Proteins (pharmacology)
• Signal Transduction
• beta-Thalassemia (metabolism)
• fas Receptor