Regulation of globin-heme balance in Diamond-Blackfan anemia by HSP70/GATA1

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Abstract
Diamond-Blackfan anemia is a congenital erythroblastopenia characterized by blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified two in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following shRNA knockdown of RPS19, RPL5 and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of other two RP mutant genes. We further documented that proteasomal degradation of HSP70, the chaperon of GATA1 is a major contributor for the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis and the decreased globin expression, all features of the severe DBA phenotype. In present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased ROS production that was more pronounced in cells of the severe phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis there by reducing free heme excess resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis. Key points Mutations in genes other than RPS19 result in significant imbalance between globin and heme synthesis leading to excess free heme. Decreased levels of HSP70 and GATA1 account for excess free heme in DBA erythroblasts; HSP70 re-expression restore the globin/heme synthesis.

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