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Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2240-2249
Red Cell Biology & its Disorders
XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia
Flavia Guillem,1,2,3 Michaël Dussiot,1,2,3* Elia Colin,1,2,3* Thunwarat Suriyun,1,2,3 Jean Benoit Arlet,1,2,3,4 Nicolas Goudin,5 Guillaume Marcion,6,7
Renaud Seigneuric,6,7 Sebastien Causse,6,7 Patrick Gonin,8 Marc Gastou,3,8,9 Marc Deloger,10 Julien Rossignol,1,11,12 Mathilde Lamarque,1,2,3
Zakia Belaid Choucair,1,2 Emilie Fleur Gautier,3,13 Sarah Ducamp,3,13
1 1,2,3† 1,2,3 Julie Vandekerckhove, Ivan C. Moura, Thiago Trovati Maciel,
6,7,14 15 3,13 15 Xiuli An, Patrick Mayeux, Narla Mohandas,
Carmen Garrido,
Geneviève Courtois1,2,3# and Olivier Hermine1,2,3,11#
1INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; 2Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; 3Laboratory of Excellence GR- ex, Paris, France; 4Service de Médecine Interne, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France; 5US24, Cell Imaging Platform, Necker Federative Structure of Research (SFR-Necker), Paris, France; 6INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer and Association pour la Recherche con- tre le Cancer, and Laboratoire d’Excellence Lipoprotéines et Santé (LipSTIC), Dijon, France; 7Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France; 8Gustave Roussy, Université Paris-Saclay, Plateforme d'Evaluation Préclinique-UMS 3655/US23, Villejuif, France; 9Université Paris 7 Denis Diderot-Sorbonne Paris Cité, Paris, France; 10Institut Curie, PSL Research University, INSERM, U 900, MINES, ParisTech, Paris, France; 11Service d’Hématologie, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris Hôpital Necker, Paris, France; 12Département d'Hématologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France; 13Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, and Plateforme de Proteomique Paris 5 (3P5), Paris, France; 14Centre Anticancéreux George François Leclerc, Dijon, France and 15Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA
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 fac- tor 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 transduc- tion 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 repre- senting a new therapeutic option to ameliorate ineffective erythropoiesis of β-TM.
*MD and EC contributed equally to this work; #GC and OH contributed equally to this work as co-senior authors. †This article is dedicated to the memory of Ivan C. Moura who passed away during its preparation.
ABSTRACT
Correspondence:
OLIVIER HERMINE
ohermine@gmail.com
Received: November 22, 2018. Accepted: November 19, 2019. Pre-published: November 21, 2019.
doi:10.3324/haematol.2018.210054 ©2020 Ferrata Storti Foundation
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