Karyopherins; Receptors, Cytoplasmic and Nuclear; exportin 1 protein; Cell Differentiation; Erythroblasts; Erythropoiesis; Humans; Karyopherins/genetics; Receptors, Cytoplasmic and Nuclear/genetics; beta-Thalassemia/drug therapy/genetics
Abstract :
[en] β-thalassemia major (β-TM) is an inherited hemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of hemoglobin, leading to the accumulation of free a-globin chains that aggregate and cause ineffective erythropoiesis. We have previously demonstrated that terminal erythroid maturation requires a transient activation of caspase-3 and that the chaperone Heat Shock Protein 70 (HSP70) accumulates in the nucleus to protect GATA-1 transcription factor from caspase-3 cleavage. This nuclear accumulation of HSP70 is inhibited in human β-TM erythroblasts due to HSP70 sequestration in the cytoplasm by free a-globin chains, resulting in maturation arrest and apoptosis. Likewise, terminal maturation can be restored by transduction of a nuclear-targeted HSP70 mutant. Here we demonstrate that in normal erythroid progenitors, HSP70 localization is regulated by the exportin-1 (XPO1), and that treatment of β-thalassemic erythroblasts with an XPO1 inhibitor increased the amount of nuclear HSP70, rescued GATA-1 expression and improved terminal differentiation, thus representing a new therapeutic option to ameliorate ineffective erythropoiesis of β-TM.
Disciplines :
Hematology
Author, co-author :
Guillem, Flavia; INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms
Dussiot, Michaël; INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms
Colin, Elia; INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms
Suriyun, Thunwarat; INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms
Arlet, Jean Benoit; INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms
Goudin, Nicolas; US24, Cell Imaging Platform, Necker Federative Structure of Research
Marcion, Guillaume ; Université de Liège - ULiège > GIGA > GIGA I3 - Hematology ; INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer
Seigneuric, Renaud; INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer
Causse, Sebastien; INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer
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