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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.

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Figure 1: RAP-011 treatment improves hematological parameters in thalassemic mice.
Figure 2: RAP-011 treatment reduces ineffective erythropoiesis in thalassemic mice.
Figure 3: RAP-011 treatment decreases iron overload and RBC-associated hemoglobin precipitates in thalassemic mice.
Figure 4: GDF11 is overexpressed in β-thalassemia and is associated with ineffective erythropoiesis.
Figure 5: ActRIIA trap therapy promotes early-stage erythroblast apoptosis in thalassemic mice.
Figure 6: GDF11 inactivation promotes terminal erythropoiesis.

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Acknowledgements

This work was supported by Agence Nationale de la Recherche (grants ANR-10-JCJC-1108, ANR-12-BSV1-0039, ANR-11-LABX-0051 and ANR-10-BLAN-1109), Assistance Publique Hôpitaux de Paris–CNRS Contrats Hospitaliers de Recherche Translationnelle, Institut National du Cancer, Cancéropôle Île-de-France, Fondation pour la Recherche Médicale, Fondation de France, Association Laurette Fugain and Association pour la Recherche sur le Cancer. The Imagine Institute and the Laboratory of Excellence GR-Ex are funded by the program 'Investissements d'avenir' of the French National Research Agency (ANR-10-IAHU-01 and ANR-11-IDEX-0005-02, respectively). We thank S. Nelson and J. Bex for technical assistance, C. Brouzes for cytological advice, M.G. Traore and N. Goudin for assistance with confocal microscopy and O. Thibaudeau, F. Watier and N. Gadessaud for assistance in histological sample processing. 34-3C IgG2a antibody was provided by S. Izui (University Medical Center, University of Geneva).

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M.D., T.T.M. and A.F. designed and performed all experiments, analyzed the data and helped write the manuscript. J.V., C.C., F.C., D.G., O.N., E. Paubelle and G.C. performed experiments and analyzed data. E. Payen, P.L. and Y.B. provided thalassemic mice, intellectual input and technical expertise for the hemoglobin analysis. J.-A.R. and J.-B.A. provided human samples. T.O.D., R.C. and V.S. participated in project planning, provided RAP-011 and ACE-011, actively contributed to the development of the project and contributed to the writing and editing of the manuscript. Y.Z.G. contributed to the writing and editing of the manuscript. O.H. and I.C.M. supervised the overall project, performed the experiments, analyzed the data and wrote the manuscript.

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Correspondence to Olivier Hermine or Ivan C Moura.

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Competing interests

T.O.D., R.C. and V.S. are employees of Celgene. This study was partially supported by a grant from Celgene (to O.H.).

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Dussiot, M., Maciel, T., Fricot, A. et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med 20, 398–407 (2014). https://doi.org/10.1038/nm.3468

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