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Nat Med. 2014 Apr;20(4):398-407. doi: 10.1038/nm.3468. Epub 2014 Mar 23.

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

Author information

1
1] INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. [3] CNRS ERL 8254, Paris, France. [4] Laboratory of Excellence GR-Ex, Paris, France. [5] INSERM U1149, Center for Research on Inflammation, Paris, France. [6].
2
1] INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. [3] CNRS ERL 8254, Paris, France. [4] Laboratory of Excellence GR-Ex, Paris, France. [5] INSERM U1149, Center for Research on Inflammation, Paris, France.
3
1] Commissariat à l'Energie Atomique (CEA)-Institut des Maladies Emergentes et des Thérapies Innovantes (iMETI), Fontenay-aux-Roses, France. [2] UMR 962 (Inserm-CEA-University of Paris-Sud), Fontenay-aux-Roses, France.
4
Laboratory of Excellence GR-Ex, Paris, France.
5
1] INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. [3] CNRS ERL 8254, Paris, France. [4] Laboratory of Excellence GR-Ex, Paris, France. [5] Département de Biothérapie, Hôpital Necker-Enfants Malades, Paris, France.
6
1] INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. [3] CNRS ERL 8254, Paris, France. [4] Laboratory of Excellence GR-Ex, Paris, France.
7
Erythropoiesis Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA.
8
Celgene, Summit, New Jersey, USA.
9
Celgene, San Francisco, California, USA.
10
1] INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris, France. [2] Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. [3] CNRS ERL 8254, Paris, France. [4] Laboratory of Excellence GR-Ex, Paris, France. [5] Service d'Hématologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.

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.

PMID:
24658077
DOI:
10.1038/nm.3468
[Indexed for MEDLINE]

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