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

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.