[en] β-Thalassaemia major (β-TM) is an inherited haemoglobinopathy caused by a quantitative defect in the synthesis of β-globin chains of haemoglobin, leading to the accumulation of free α-globin chains that form toxic aggregates. Despite extensive knowledge of the molecular defects causing β-TM, little is known of the mechanisms responsible for the ineffective erythropoiesis observed in the condition, which is characterized by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage. We have previously demonstrated that normal human erythroid maturation requires a transient activation of caspase-3 at the later stages of maturation. Although erythroid transcription factor GATA-1, the master transcriptional factor of erythropoiesis, is a caspase-3 target, it is not cleaved during erythroid differentiation. We have shown that, in human erythroblasts, the chaperone heat shock protein70 (HSP70) is constitutively expressed and, at later stages of maturation, translocates into the nucleus and protects GATA-1 from caspase-3 cleavage. The primary role of this ubiquitous chaperone is to participate in the refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation. Here we show in vitro that during the maturation of human β-TM erythroblasts, HSP70 interacts directly with free α-globin chains. As a consequence, HSP70 is sequestrated in the cytoplasm and GATA-1 is no longer protected, resulting in end-stage maturation arrest and apoptosis. Transduction of a nuclear-targeted HSP70 mutant or a caspase-3-uncleavable GATA-1 mutant restores terminal maturation of β-TM erythroblasts, which may provide a rationale for new targeted therapies of β-TM.
Disciplines :
Hematology
Author, co-author :
Arlet, Jean-Benoît; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Ribeil, Jean-Antoine; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Guillem, Flavia; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Negre, Olivier; Commissariat à l'énergie atomique (CEA), Institute of Emerging Diseases and
Hazoume, Adonis; 1] INSERM, unité mixte de recherche 866, Equipe labellisée Ligue contre le Cancer
Marcion, Guillaume ; Université de Liège - ULiège > GIGA > GIGA I3 - Hematology ; 1] INSERM, unité mixte de recherche 866, Equipe labellisée Ligue contre le Cancer
Beuzard, Yves; Commissariat à l'énergie atomique (CEA), Institute of Emerging Diseases and
Dussiot, Michaël; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Moura, Ivan Cruz; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Demarest, Samuel; Centre national de la recherche scientifique (CNRS), unité mixte de recherche
de Beauchêne, Isaure Chauvot; 1] Centre national de la recherche scientifique (CNRS), unité mixte de recherche
Belaid-Choucair, Zakia; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Sevin, Margaux; 1] INSERM, unité mixte de recherche 866, Equipe labellisée Ligue contre le Cancer
Maciel, Thiago Trovati; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Auclair, Christian; 1] Centre national de la recherche scientifique (CNRS), unité mixte de recherche
Leboulch, Philippe; 1] Commissariat à l'énergie atomique (CEA), Institute of Emerging Diseases and
Chretien, Stany; Commissariat à l'énergie atomique (CEA), Institute of Emerging Diseases and
Tchertanov, Luba; 1] Centre national de la recherche scientifique (CNRS), unité mixte de recherche
Baudin-Creuza, Véronique; INSERM, unité mixte de recherche 779, Université Paris XI, Le Kremlin-Bicêtre,
Seigneuric, Renaud; University of Burgundy, Faculty of Medicine and Pharmacy, 7 boulevard Jeanne
Fontenay, Michaela; 1] Laboratory of Excellence GR-Ex, 75015 Paris, France [2] Institut Cochin,
Garrido, Carmen; 1] INSERM, unité mixte de recherche 866, Equipe labellisée Ligue contre le Cancer
Hermine, Olivier; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
Courtois, Geneviève; 1] Laboratoire INSERM, unité mixte de recherche 1163, centre national de la
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