XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia

• Published in: Haematologica (Roma) 2020-09, Vol.105 (9), p.2240-2249
• Main Authors: Guillem, Flavia, Dussiot, Michaël, Colin, Elia, Suriyun, Thunwarat, Arlet, Jean Benoit, Goudin, Nicolas, Marcion, Guillaume, Seigneuric, Renaud, Causse, Sebastien, Gonin, Patrick, Gastou, Marc, Deloger, Marc, Rossignol, Julien, Lamarque, Mathilde, Choucair, Zakia Belaid, Gautier, Emilie Fleur, Ducamp, Sarah, Vandekerckhove, Julie, Moura, Ivan C, Maciel, Thiago Trovati, Garrido, Carmen, An, Xiuli, Mayeux, Patrick, Mohandas, Narla, Courtois, Geneviève, Hermine, Olivier
• Format: Article
• Language: English
• Subjects: beta-Thalassemia - drug therapy; beta-Thalassemia - genetics; beta-Thalassemia/drug therapy/genetics; Cell Differentiation; Erythroblasts; Erythropoiesis; Exportin 1 Protein; Hematology; Human health and pathology; Human health sciences; Humans; Hématologie; Karyopherins; Karyopherins - genetics; Life Sciences; Receptors, Cytoplasmic and Nuclear; Receptors, Cytoplasmic and Nuclear - genetics; Sciences de la santé humaine
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2018.210054

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.