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

Marc Gastou; Sarah Rio; Michael Dussiot; Narjesse Karboul; Hélène Moniz; Thierry Leblanc; Margaux Sevin; Patrick Gonin; Jérôme Larghero; Carmen Garrido; Aupama Narla; Narla Mohandas; William Vainchenker; Olivier Hermine; Eric Solary; Lydie da Costa

doi:10.1182/bloodadvances.2017008078

Article dans une revue

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 ^{3, 11, *}

* Auteur correspondant

1 U1170 Inserm - Hématopoïèse normale et pathologique

2 Labex Gr-Ex - Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge

3 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation

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 A2T - Alloimmunité-Autoimmunité-Transplantation

9 Stanford University School of Medicine [Stanford]

10 Red Cell Physiology Laboratory [New York, USA]

11 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

Type de document :

Article dans une revue

Domaine :

Sciences du Vivant [q-bio] / Médecine humaine et pathologie / Hématologie

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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01663646
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : jeudi 14 décembre 2017 - 10:34:15
Dernière modification le : mercredi 16 septembre 2020 - 17:51:07

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

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