An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia.
An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia.
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DOI：
10.1038/nm.3468
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发表时间：
2014-04
期刊：
影响因子：
82.9
通讯作者：
Moura IC
中科院分区：
文献类型：
--
作者：
Dussiot M;Maciel TT;Fricot A;Chartier C;Negre O;Veiga J;Grapton D;Paubelle E;Payen E;Beuzard Y;Leboulch P;Ribeil JA;Arlet JB;Coté F;Courtois G;Ginzburg YZ;Daniel TO;Chopra R;Sung V;Hermine O;Moura IC
β-地中海贫血患者无效红细胞生成的病理生理学机制尚不清楚。我们报道，激活素受体IIA(ActRIIA)配体陷阱RAP-011可以改善β-地中海贫血小鼠模型的无效红细胞生成、纠正贫血和限制铁超载。生长分化因子11(GDF11)是一种ActRIIA配体，在地中海贫血小鼠的脾红细胞和β-地中海贫血患者的红细胞和血清中表达增加。GDF11的失活降低了氧化应激和α-珠蛋白膜沉淀物的数量，导致红系终末分化增加。GDF11的异常表达依赖于活性氧，提示β-地中海贫血存在自分泌扩增环。GDF11失活还通过Fas-Fas配体途径诱导幼稚红细胞凋亡，纠正幼稚/成熟红细胞比例异常。综上所述，这些观察表明，ActRIIA配体陷阱可能通过抑制GDF11的有害影响而在β-地中海贫血中具有治疗意义。GDF11是一种细胞因子，通过涉及氧化应激和α-珠蛋白沉淀的自分泌放大环路阻止红系终末成熟。
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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