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

M Dussiot, TT Maciel, A Fricot, C Chartier, O Negre… - Nature medicine, 2014 - nature.com
M Dussiot, TT Maciel, A Fricot, C Chartier, O Negre, J Veiga, D Grapton, E Paubelle…
Nature medicine, 2014nature.com
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 …
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.
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