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

Gastou, Marc; Rio, Sarah; Dussiot, Michaël; Karboul, Narjesse; Moniz, Hélène; Leblanc, Thierry; Sevin, Margaux; Gonin, Patrick; Larghero, Jérôme; Garrido, Carmen; Narla, Anupama; Mohandas, Narla; Vainchenker, William; Hermine, Olivier; Solary, Éric; Costa, Lydie Da

doi:10.1182/bloodadvances.2017008078

Cited by 37 publications

(57 citation statements)

References 64 publications

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“…This GATA1 protective mechanism appears to break down in hematological disorders manifesting with IE, such as DBA and MDS. In DBA, it was recently shown that HSP70 protein is downregulated due to its increased ubiquitination and proteasomal degradation in RPL11‐ and RPL5‐deficient human primary erythroid cells, but not in RPS19‐deficient cells, resulting in proliferation and differentiation defects and increased apoptosis in erythroid cells, resembling DBA features . A subsequent study showed a disequilibrium of globin chain and heme synthesis in RPL11‐ and RPL5‐deficient human erythroid cells, resulting in excessive free heme which downregulated HSP70 protein .…”

Section: Downregulation Of Gata1 Protein Levels and Ineffective Erythmentioning

confidence: 97%

“…The study by Doty et al also suggests that aberrant accumulation of heme, contributes to the amplification of RP imbalance, thus causing premature downregulation of GATA1 levels, responsible for the IE that is characteristic of DBA and MDS . Hence, it is clear in that in DBA, HSP70 downregulation results in a significant drop in GATA1 protein levels due to caspase‐mediated cleavage, which underlies the observed erythroid maturation defects . The HSP70 mediated protection of GATA1 is also disrupted in β‐thalassemia, which also manifests with IE.…”

Section: Downregulation Of Gata1 Protein Levels and Ineffective Erythmentioning

confidence: 99%

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Regulation of GATA1 levels in erythropoiesis

et al. 2019

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GATA1 is considered as the "master" transcription factor in erythropoiesis. It regulates at the transcriptional level all aspects of erythroid maturation and function, as revealed by gene knockout studies in mice and by genome-wide occupancies in erythroid cells. The GATA1 protein contains two zinc finger domains and an N-terminal transactivation domain. GATA1 translation results in the production of the full-length protein and of a shorter variant (GATA1s) lacking the N-terminal transactivation domain, which is functionally deficient in supporting erythropoiesis. GATA1 protein abundance is highly regulated in erythroid cells at different levels, including transcription, mRNA translation, posttranslational modifications, and protein degradation, in a differentiationstage-specific manner. Maintaining high GATA1 protein levels is essential in the early stages of erythroid maturation, whereas downregulating GATA1 protein levels is a necessary step in terminal erythroid differentiation. The importance of maintaining proper GATA1 protein homeostasis in erythropoiesis is demonstrated by the fact that both GATA1 loss and its overexpression result in lethal anemia. Importantly, alterations in any of those GATA1 regulatory checkpoints have been recognized as an important cause of hematological disorders such as dyserythropoiesis (with or without thrombocytopenia), β-thalassemia, Diamond-Blackfan anemia, myelodysplasia, or leukemia. In this review, we provide an overview of the multilevel regulation of GATA1 protein homeostasis in erythropoiesis and of its deregulation in hematological disease. K E Y W O R D S

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Section: Downregulation Of Gata1 Protein Levels and Ineffective Erythmentioning

confidence: 97%

Section: Downregulation Of Gata1 Protein Levels and Ineffective Erythmentioning

confidence: 99%

Regulation of GATA1 levels in erythropoiesis

et al. 2019

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“…Ludwig et al 53 have shown that GATA1 transcripts are specifically less translated compared to others in DBA owing to a higher threshold for initiation of translation of GATA1 mRNA due to defective ribosomal biogenesis. Gastou et al 54 showed that HSP70, the chaperon of GATA1, is degraded by the proteasome following polyubiquitination during the BFU-E and CFU-E stages of erythropoiesis. Decreased HSP70 expression has been noted in all of the RP mutated-gene-tested DBA patients and in shRNA models other than RPS19, which exhibit a normal expression of HSP70.…”

Section: Molecular Diagnosismentioning

confidence: 99%

“…This correlates perfectly with the low level of induced apoptosis in these RPS19-mutated DBA patients compared to the RPL5- or RPL11-mutated ones. Interestingly, HSP70 degradation is responsible for caspase-3-dependent GATA1 cleavage during terminal erythroid differentiation and the resultant decreased GATA1 protein expression at late stages of erythroid differentiation 54 . Finally, the EPO gene has been found to be mutated in one consanguineous Turkish family in the USA, with a homozygous missense mutation in exon 5 of EPO .…”

Section: Molecular Diagnosismentioning

confidence: 99%

An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

2018

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Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

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“…Two recent papers suggest that decrease of GATA1 full-length protein resulting from RP haploinsufficiency and deficiency of HSP70 can disturb the balance of globin-heme and leads to the accumulation of free cytoplasmic heme in erythroid progenitors, which can cause increase of P53-dependent apoptosis of DBA erythroid cells. [119][120][121] Of note, unlike in the presence of RP mutations in DBA patients, accumulation of heme upon only FLVCR1 depletion causes P53-independent apoptosis. 120 Finally, work by Bodine and colleagues suggest yet another model for pathogenesis of DBA.…”

Section: Gata1 Mutations In Dbamentioning

confidence: 99%

GATA1 mutations in red cell disorders

Ling

Crispino

2019

IUBMB Life

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GATA1 is an essential regulator of erythroid cell gene expression and maturation.In its absence, erythroid progenitors are arrested in differentiation and undergo apoptosis. Much has been learned about GATA1 function through animal models, which include genetic knockouts as well as ones with decreased levels of expression. However, even greater insights have come from the finding that a number of rare red cell disorders, including Diamond-Blackfan anemia, are associated with GATA1 mutations. These mutations affect the amino-terminal zinc finger (N-ZF) and the amino-terminus of the protein, and in both cases can alter the DNA-binding activity, which is primarily conferred by the third functional domain, the carboxylterminal zinc finger (C-ZF). Here we discuss the role of GATA1 in erythropoiesis with an emphasis on the mutations found in human patients with red cell disorders. K E Y W O R D Sanemia, erythropoiesis, GATA1

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

Abstract: Key Points• Proteasomal HSP70 degradation results in cleavage of GATA1, decrease in erythroid progenitors, and apoptosis in severe DBA phenotype.• HSP70 plays a role not only during terminal erythroid differentiation, but also in the earlier proliferation of erythroid progenitor cells.

Cited by 37 publications

References 64 publications

Regulation of GATA1 levels in erythropoiesis

Regulation of GATA1 levels in erythropoiesis

An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

GATA1 mutations in red cell disorders

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