The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70.
Fiche publication
Date publication
octobre 2017
Journal
Blood advances
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen
Tous les auteurs :
Gastou M, Rio S, Dussiot M, Karboul N, Moniz H, Leblanc T, Sevin M, Gonin P, Larghéro J, Garrido C, Narla A, Mohandas N, Vainchenker W, Hermine O, Solary E, Da Costa L, ,
Lien Pubmed
Résumé
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 phenotype is more severe than RPS19 phenotype because of delayed erythroid differentiation and increased apoptosis of RPL11 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 erythroid cells while being preserved in RPS19 cells. The decreased expression of HSP70 in RPL11 cells is related to an enhanced proteasomal degradation of polyubiquitinylated HSP70. Restoration of HSP70 expression level in RPL11 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.
Référence
Blood Adv. 2017 10 10;1(22):1959-1976