title: 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.
authors.affiliation: 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].
authors.forename: Michael
authors.initials: M
authors.lastname: Dussiot
authors.affiliation: 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].
authors.forename: Thiago T
authors.initials: TT
authors.lastname: Maciel
authors.affiliation: 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.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fricot
authors.affiliation: 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.
authors.forename: Céline
authors.initials: C
authors.lastname: Chartier
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Negre
authors.affiliation: Laboratory of Excellence GR-Ex, Paris, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Veiga
authors.affiliation: 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.
authors.forename: Damien
authors.initials: D
authors.lastname: Grapton
authors.affiliation: 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.
authors.forename: Etienne
authors.initials: E
authors.lastname: Paubelle
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Payen
authors.affiliation: 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.
authors.forename: Yves
authors.initials: Y
authors.lastname: Beuzard
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.affiliation: 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.
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.affiliation: 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.
authors.forename: Jean-Benoit
authors.initials: JB
authors.lastname: Arlet
authors.affiliation: 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.
authors.forename: Francine
authors.initials: F
authors.lastname: Coté
authors.affiliation: 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.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Courtois
authors.affiliation: Erythropoiesis Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA.
authors.forename: Yelena Z
authors.initials: YZ
authors.lastname: Ginzburg
authors.affiliation: Celgene, Summit, New Jersey, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Celgene, Summit, New Jersey, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Celgene, San Francisco, California, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: 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.
authors.forename: Ivan C
authors.identifier: 0000000284182803
authors.initials: IC
authors.lastname: Moura
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000378:metabolism*; D004920:Erythropoiesis / Q000187:drug effects*; D053222:Fas Ligand Protein; D005784:Gene Amplification / Q000502:physiology; D055412:Growth Differentiation Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006397:Hematinics / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction; D017086:beta-Thalassemia / Q000378:metabolism*; D019014:fas Receptor
chemical_list: D030301:Activin Receptors, Type II; D019485:Bone Morphogenetic Proteins; D053222:Fas Ligand Protein; D055412:Growth Differentiation Factors; D006397:Hematinics; D008024:Ligands; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C542017:sotatercept; C492266:GDF11 protein, human; C119153:Gdf11 protein, mouse; C425585:activin receptor type II-A