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

ABSTRACT: Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34⁺ cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34⁺ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of 2 other ribosomal protein (RP) mutant genes. We further documented that proteasomal degradation of HSP70, the chaperone of GATA1, is a major contributor to the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis, and decreased globin expression, which are all features of the RPL5 or RPL11 DBA phenotype. In the 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 reactive oxygen species production that was more pronounced in cells of the RPL5 or RPL11 phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis thereby reducing free heme excess and 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.

SUBMITTER: Rio S

PROVIDER: S-EPMC6428670 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Rio Sarah S Gastou Marc M Karboul Narjesse N Derman Raphaёl R Suriyun Thunwarat T Manceau Hana H Leblanc Thierry T El Benna Jamel J Schmitt Caroline C Azouzi Slim S Larghéro Jérome J Karim Zoubida Z Macias-Garcia Alejandra A Chen Jane-Jane JJ Hermine Olivier O Courtois Geneviève G Puy Hervé H Gouya Laurent L Mohandas Narla N Da Costa Lydie L

Blood 20190130 12

Diamond-Blackfan anemia (DBA) is a congenital erythroblastopenia that is characterized by a blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified 2 in vitro erythroid cell growth phenotypes for primary CD34<sup>+</sup> cells from DBA patients and following short hairpin RNA knockdown of RPS19, RPL5, and RPL11 expression in normal human CD34<sup>+</sup> cells. The haploinsufficient RPS19 in ...[more]

PMID: 30700418

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Project description:Diamond Blackfan Anemia (DBA) is a rare, congenital erythrocyte aplasia that is usually caused by haploinsufficiency of ribosomal proteins due to diverse mutations in one of several ribosomal protein genes. A striking feature of this disease is that a range of different mutations in ribosomal proteins results in similar disease phenotypes primarily characterized by erythrocyte abnormalities and macrocytic anemia, while most other cell types are minimally affected. Previously, we analyzed the erythrocyte membrane proteomes of several DBA patients and identified several proteins that are not typically associated with this cell type that suggested inflammatory mechanisms contribute to the pathogenesis of DBA. In this study, we evaluated the erythrocyte cytosolic proteome of DBA patients through in-depth analysis of hemoglobin-depleted erythrocyte cytosol. The simple, reproducible, hemoglobin depletion using nickel columns enabled in-depth analysis of over 1000 cytosolic erythrocyte proteins with minimal subsequent fractionation of the proteome. Label-free quantitation and statistical analysis identified 29 proteins that were significantly changed in DBA patients compared to matched healthy control donors. Some of the proteins that were significantly increased in DBA erythrocyte cytoplasm included three proteasome subunit beta proteins that make up the immunoproteasome and proteins induced by interferon-γ such as n-myc interactor and interferon-induced 25 kDa protein [NMI and IFI35 respectively]. Pathway analysis confirmed the presence of an inflammatory signature with erythrocytes of DBA patients and predicted key upstream regulators including mitogen activated kinase 1, interferon-γ, tumor suppressor p53, and tumor necrosis factor. These results show that erythrocytes in DBA patients are intrinsically different from those in healthy controls which may be due to an inflammatory response resulting from the inherent molecular defect of ribosomal protein haploinsufficiency or changes in the bone marrow microenvironment that leads to red cell aplasia in DBA patients.

Dataset Information

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

Publications

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

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