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 withmutations 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,2,3 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.