Haematologica (Nov 2019)
XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia
- Flavia Guillem,
- Michaël Dussiot,
- Elia Colin,
- Thunwarat Suriyun,
- Jean Benoit Arlet,
- Nicolas Goudin,
- Guillaume Marcion,
- Renaud Seigneuric,
- Sebastien Causse,
- Patrick Gonin,
- Marc Gastou,
- Marc Deloger,
- Julien Rossignol,
- Mathilde Lamarque,
- Zakia Belaid Choucair,
- Emilie Fleur Gautier,
- Sarah Ducamp,
- Julie Vandekerckhove,
- Ivan C. Moura,
- Thiago Trovati Maciel,
- Carmen Garrido,
- Xiuli An,
- Patrick Mayeux,
- Narla Mohandas,
- Geneviève Courtois,
- Olivier Hermine
Affiliations
- Flavia Guillem
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Michaël Dussiot
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Elia Colin
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Thunwarat Suriyun
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Jean Benoit Arlet
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France; Service de Médecine Interne, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
- Nicolas Goudin
- US24, Cell Imaging Platform, Necker Federative Structure of Research (SFR-Necker), Paris, France
- Guillaume Marcion
- INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d’Excellence Lipoprotéines et Santé (LipSTIC), Dijon, France; Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France
- Renaud Seigneuric
- INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d’Excellence Lipoprotéines et Santé (LipSTIC), Dijon, France; Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France
- Sebastien Causse
- INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d’Excellence Lipoprotéines et Santé (LipSTIC), Dijon, France; Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France
- Patrick Gonin
- Gustave Roussy, Université Paris-Saclay, Plateforme d'Evaluation Préclinique-UMS 3655/US23, Villejuif, France
- Marc Gastou
- Laboratory of Excellence GRex, Paris, France; Gustave Roussy, Université Paris-Saclay, Plateforme d'Evaluation Préclinique-UMS 3655/US23, Villejuif, France; Université Paris 7 Denis Diderot-Sorbonne Paris Cité, Paris, France
- Marc Deloger
- Institut Curie, PSL Research University, INSERM, U 900, MINES, ParisTech, Paris, France
- Julien Rossignol
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Service d’Hématologie, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris Hôpital Necker, Paris, France; Département d'Hématologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Mathilde Lamarque
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Zakia Belaid Choucair
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France
- Emilie Fleur Gautier
- Laboratory of Excellence GRex, Paris, France; Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, and Plateforme de Proteomique Paris 5 (3P5), Paris, France
- Sarah Ducamp
- Laboratory of Excellence GRex, Paris, France; Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, and Plateforme de Proteomique Paris 5 (3P5), Paris, France
- Julie Vandekerckhove
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France
- Ivan C. Moura
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Thiago Trovati Maciel
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Carmen Garrido
- INSERM, Unité Mixte de Recherche 866, Equipe Labellisée Ligue Contre le Cancer and Association pour la Recherche contre le Cancer, and Laboratoire d’Excellence Lipoprotéines et Santé (LipSTIC), Dijon, France; Faculty of Medicine and Pharmacy, University of Burgundy, Dijon, France; Centre Anticancéreux George François Leclerc, Dijon, France
- Xiuli An
- Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA
- Patrick Mayeux
- Laboratory of Excellence GRex, Paris, France; Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, and Plateforme de Proteomique Paris 5 (3P5), Paris, France
- Narla Mohandas
- Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA
- Geneviève Courtois
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France
- Olivier Hermine
- INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris, France; Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France; Laboratory of Excellence GRex, Paris, France; Service d’Hématologie, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris Hôpital Necker, Paris, France
- DOI
- https://doi.org/10.3324/haematol.2018.210054
- Journal volume & issue
-
Vol. 105,
no. 9
Abstract
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.
