The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70

Marc Gastou 1, 2 Sarah Rio 2, 3 Michael Dussiot 2, 4 Narjesse Karboul 2, 3 Hélène Moniz 1 Thierry Leblanc 5 Margaux Sevin 2, 6 Patrick Gonin 7 Jérôme Larghero 8 Carmen Garrido 2, 6 Aupama Narla 9 Narla Mohandas 10 William Vainchenker 1, 2 Olivier Hermine 4, 2 Eric Solary 1 Lydie Da Costa 11, 12, *
* Auteur correspondant
1 U1170 Inserm - Hématopoïèse normale et pathologique
2 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge
3 Centre de recherche sur l'inflamation - UMR 1149
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris]
6 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
7 PFEP - Plateforme d’évaluation préclinique
AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
8 Hôpital Saint-Louis, Unité de Thérapie Cellulaire
9 Stanford University School of Medicine [Stanford]
10 Red Cell Physiology Laboratory [New York, USA]
11 CRI - Centre de recherche sur l'Inflammation
12 Service d'Hématologie Biologique [Hôpital Robert Debré, Paris]
Abstract : Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome that exhibits an erythroid-specific phenotype. In at least 70% of cases, DBA is related to a haploinsufficient germ line mutation in a ribosomal protein (RP) gene. Additional cases have been associated with mutations in GATA1. We have previously established that the RPL11+/Mut phenotype is more severe than RPS19+/Mut phenotype because of delayed erythroid differentiation and increased apoptosis of RPL11+/Mut erythroid progenitors. The HSP70 protein is known to protect GATA1, the major erythroid transcription factor, from caspase-3 mediated cleavage during normal erythroid differentiation. Here, we show that HSP70 protein expression is dramatically decreased in RPL11+/Mut erythroid cells while being preserved in RPS19+/Mut cells. The decreased expression of HSP70 in RPL11+/Mut cells is related to an enhanced proteasomal degradation of polyubiquitinylated HSP70. Restoration of HSP70 expression level in RPL11+/Mut cells reduces p53 activation and rescues the erythroid defect in DBA. These results suggest that HSP70 plays a key role in determining the severity of the erythroid phenotype in RP-mutation–dependent DBA.
Keywords : Hsp70 Apoptosis-Inducing Factor Protein Gene Deletions Human Erythroblasts Ribosomal-Proteins Inhibits Apoptosis Gata1 Mutations Nuclear Import Erythropoiesis Identification
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Article dans une revue
Blood Advances, The American Society of Hematology, 2017, 1 (22), pp.1959 - 1976. 〈http://www.bloodadvances.org/content/1/22/1959?sso-checked=true〉. 〈10.1182/bloodadvances.2017008078〉
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Contributeur : Lnc - Université de Bourgogne <>
Soumis le : jeudi 14 décembre 2017 - 10:34:15
Dernière modification le : mercredi 28 mars 2018 - 13:12:03

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Marc Gastou, Sarah Rio, Michael Dussiot, Narjesse Karboul, Hélène Moniz, et al.. The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70. Blood Advances, The American Society of Hematology, 2017, 1 (22), pp.1959 - 1976. 〈http://www.bloodadvances.org/content/1/22/1959?sso-checked=true〉. 〈10.1182/bloodadvances.2017008078〉. 〈hal-01663646〉

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