The Severe Phenotype of Diamond-Blackfan Anemia is Modulated by Heat Shock Protein 70

Overview

Journal Blood Adv

Specialty Hematology

Date 2018 Jan 4

PMID 29296843

Citations 23

Authors

Marc Gastou

Sarah Rio

Michael Dussiot

Narjesse Karboul

Helene Moniz

Thierry Leblanc

Margaux Sevin

Patrick Gonin

Jerome Larghero

Carmen Garrido

Anupama Narla

Narla Mohandas

William Vainchenker

Olivier Hermine

Eric Solary

Lydie Da Costa

Affiliations

Soon will be listed here.

Abstract

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 phenotype is more severe than RPS19 phenotype because of delayed erythroid differentiation and increased apoptosis of RPL11 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 erythroid cells while being preserved in RPS19 cells. The decreased expression of HSP70 in RPL11 cells is related to an enhanced proteasomal degradation of polyubiquitinylated HSP70. Restoration of HSP70 expression level in RPL11 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.

Citing Articles

An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants.

Fellmann F, Saunders C, ODonohue M, Reid D, McFadden K, Montel-Lehry N JCI Insight. 2024; 9(17).

PMID: 39088281 PMC: 11385091. DOI: 10.1172/jci.insight.172475.

A De Novo Frameshift Mutation in RPL5 with Classical Phenotype Abnormalities and Worsening Anemia Diagnosed in a Young Adult-A Case Report and Review of the Literature.

Dorenkamp M, Porret N, Diepold M, Rovo A Medicina (Kaunas). 2023; 59(11).

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Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia.

Liu Y, Karlsson S Leukemia. 2023; 38(1):1-9.

PMID: 37973818 PMC: 10776401. DOI: 10.1038/s41375-023-02082-w.

Plasmodium falciparum infection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis.

Feldman T, Ryan Y, Egan E Blood Adv. 2023; 7(18):5496-5509.

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The transcriptomic landscape of normal and ineffective erythropoiesis at single-cell resolution.

Doty R, Lausted C, Munday A, Yang Z, Yan X, Meng C Blood Adv. 2023; 7(17):4848-4868.

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