An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia
Open accessAbstract
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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Clinical trials are showing that correcting ineffective erythropoiesis by activin ligand traps not only improves anemia but, in the long-term, also iron loading in both non-transfusion-dependent and transfusion-dependent thalassemia and ringed sideroblast myelodysplastic syndrome.
“Clinical trials are showing that correcting ineffective erythropoiesis by activin ligand traps128 not only improves anemia but, in the long-term, also iron loading in both non-transfusion-dependent and transfusion-dependent thalassemia129 and ringed sideroblast myelodysplastic syndrome.130”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [128]
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- Authors
- Dussiot, M., Maciel, T. T., Fricot, A., Chartier, C., Negre, O., Veiga, J., Grapton, D., Paubelle, E., Payen, E., Beuzard, Y., Leboulch, P., Ribeil, J.-A., Arlet, J.-B., Coté, F., Courtois, G., Ginzburg, Y. Z., Daniel, T. O., Chopra, R., Sung, V., Hermine, O., & Moura, I. C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Laboratory of Excellence GR-Ex (FR)
- Université Paris-Sud (FR)
- Hôpital Necker-Enfants Malades (FR)
- New York Blood Center (US)
- Celgene (United States) (US)
- Corresponding author
- Hermine, Olivier
- Moura, Ivan C
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-03-23
- Volume
- 20
- Issue
- 4
- Pages
- 398-407
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7730561
- OpenAlex
- W2149986474
- Cited by
- 279
- References
- 1
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 11 · 2023: 13 · 2022: 15 · 2021: 21 · 2020: 31 · 2019: 32 · 2018: 31 · 2017: 28 · 2016: 31 · 2015: 28 · 2014: 16
- FWCI
- 17.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Institut des maladies génétiques Imagine
- Agence Nationale de la Recherche (ANR-11-LABX-0051, ANR-12-BSV1-0039, ANR-10-IAHU-0001, ANR-10-BLAN-1109, ANR-11-IDEX-0005, ANR-10-JCJC-1108)
- Assistance Publique - Hôpitaux de Paris
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Assistance publique-Hôpitaux de Paris
- National Heart, Lung, and Blood Institute (K08HL105682)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095112)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- beta-thalassemia, beta-thalassemia intermedia, GDF11, ineffective erythropoiesis, terminal erythroid differentiation, Fas/Fas ligand pathway, oxidative stress, iron overload, anemia
- MeSH terms
- Animals, Cell Differentiation, Disease Models, Animal, Erythroblasts, Erythropoiesis, Gene Amplification, Hematinics, Ligands, Recombinant Fusion Proteins, Signal Transduction, beta-Thalassemia, Apoptosis, Reactive Oxygen Species, Oxidative Stress, fas Receptor, Bone Morphogenetic Proteins, Autocrine Communication, Activin Receptors, Type II, Mice, Fas Ligand Protein, Growth Differentiation Factors
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