Heat Shock Protein 70 (HSP70), one of the major key factors in Diamond-Blackfan anemia
EHA Library. Da Costa L. 06/14/17; 185057
Topic: 1Bd Other inherited bone marrow failure syndromes (e.g. Blackfan-Diamond, Dyskeratosis congenital, Telomere diseases)
Lydie Da Costa
Contributions
Contributions
Learning Objectives
Stephen Menzel - Chair Introduction
Two papers included here are investigating the relationship between iron overload and erythropoiesis from two different angles. The first (1), by Dr Ginzburg, reviews how our knowledge in this area is advanced through studies in beta-thalassaemic mice, focusing on novel findings on the role of apo-transferrin and transferrin receptor TfR1. The second (2), by Drs Angelucci and Pilo, is focused on present practical implications of established knowledge, specifically how to competently combat iron overload and its detrimental effects in the context of hematopoietic stem-cell transplantation. A third paper (3), by Dr Da Costa, is presenting new findings on pathogenetic pathways for Diamond-Blackfan anaemia.
(1) The importance of mutual interaction between erythropoiesis and iron metabolism is well recognized. Erythroferrone signalling from the bone marrow, indicating erythropoietic demand, suppresses hepcidin release from the liver, with subsequent increase in iron absorption and recycling. While iron provision is essential for erythropoiesis, iron overload is thought to exacerbate ineffective erythropoiesis in beta thalassemia through the accumulation and toxicity of reactive oxygen species in the bone marrow.
The in-depth study of the underlying processes in beta-thalassaemic mice has shown that our understanding is far from complete. Recent findings demonstrate that exogenous apo-transferrin in these mice ameliorates ineffective erythropoiesis and suppresses hepcidin release. The key mediator appears to be a reduction in effective TfR1 in erythroid precursors. The exact mechanism has not been elucidated, but implications for new therapeutic strategies can be derived.
(2) Iron overload and cellular iron toxicity have been demonstrated to influence the outcome of hematopoietic stem cell transplantation. Sustained iron overload, subsequent labile plasma iron affecting labile cellular iron and, consequently, the formation of reactive oxygen species lead to cytotoxic injury of transplanted cells and hematopoietic niche in the recipient. Focus of iron chelation therapy therefore needs to be the reversal of acute and accumulated iron overload in the recipient before and after transplantation.
(3) In Diamond-Blackfan anaemia, mutations in ribosomal-protein genes, subsequent ribosome biogenesis impairment and erythroblastopenia are well established components of the pathogenetic process, but the exact nature of the link between them is still not fully understood. While the important involvement of p53 has been shown, p53-independent has been identified and mutations in other genes found to underlie the condition. Recently, HSP70 has been identified as a key factor in its pathophysiology, being depressed in patients harbouring specific ribosomal mutations, while rectifying pathological processes when overexpressed in vitro.
Learning Objectives of the manuscript
After viewing this presentation the participant will be able to:
- (1) To review the interplay of iron overload, ineffective erythropoiesis, hepcidin and erythroferrone in beta thalassaemia including new findings obtained from the study of beta thalassaemic mice.
- Discuss the suggested role of circulating apo-transferrin and transferrin receptor TfR1 in counteracting ineffective erythropoiesis and hepcidin repression, leading to potential novel therapeutic approaches.
- (2) To review how our recently-improved understanding of iron toxicity informs strategies for iron chelation therapy before and after bone-marrow transplantation, but also becoming aware of how impending diagnostic advances could require a modification of these strategies in the near future.
- (3) Discuss recent findings on the pathophysiology of Diamond-Blackfan anaemia.
Learning Objectives of the presentation
After viewing this presentation the participant will be able to:
- DBA is a congenital erythroblastopenia amongst the inherited bone marrow failure syndromes (IBMFS), highly heterogenous in phenotype and genotype.
- DBA is the first ribosomopathy described and p53 stabilization is involved in DBA erythroblastopenia.
- HSP70 is one of the major key factors involved in DBA pathophysiology.
Two papers included here are investigating the relationship between iron overload and erythropoiesis from two different angles. The first (1), by Dr Ginzburg, reviews how our knowledge in this area is advanced through studies in beta-thalassaemic mice, focusing on novel findings on the role of apo-transferrin and transferrin receptor TfR1. The second (2), by Drs Angelucci and Pilo, is focused on present practical implications of established knowledge, specifically how to competently combat iron overload and its detrimental effects in the context of hematopoietic stem-cell transplantation. A third paper (3), by Dr Da Costa, is presenting new findings on pathogenetic pathways for Diamond-Blackfan anaemia.
(1) The importance of mutual interaction between erythropoiesis and iron metabolism is well recognized. Erythroferrone signalling from the bone marrow, indicating erythropoietic demand, suppresses hepcidin release from the liver, with subsequent increase in iron absorption and recycling. While iron provision is essential for erythropoiesis, iron overload is thought to exacerbate ineffective erythropoiesis in beta thalassemia through the accumulation and toxicity of reactive oxygen species in the bone marrow.
The in-depth study of the underlying processes in beta-thalassaemic mice has shown that our understanding is far from complete. Recent findings demonstrate that exogenous apo-transferrin in these mice ameliorates ineffective erythropoiesis and suppresses hepcidin release. The key mediator appears to be a reduction in effective TfR1 in erythroid precursors. The exact mechanism has not been elucidated, but implications for new therapeutic strategies can be derived.
(2) Iron overload and cellular iron toxicity have been demonstrated to influence the outcome of hematopoietic stem cell transplantation. Sustained iron overload, subsequent labile plasma iron affecting labile cellular iron and, consequently, the formation of reactive oxygen species lead to cytotoxic injury of transplanted cells and hematopoietic niche in the recipient. Focus of iron chelation therapy therefore needs to be the reversal of acute and accumulated iron overload in the recipient before and after transplantation.
(3) In Diamond-Blackfan anaemia, mutations in ribosomal-protein genes, subsequent ribosome biogenesis impairment and erythroblastopenia are well established components of the pathogenetic process, but the exact nature of the link between them is still not fully understood. While the important involvement of p53 has been shown, p53-independent has been identified and mutations in other genes found to underlie the condition. Recently, HSP70 has been identified as a key factor in its pathophysiology, being depressed in patients harbouring specific ribosomal mutations, while rectifying pathological processes when overexpressed in vitro.
Learning Objectives of the manuscript
After viewing this presentation the participant will be able to:
- (1) To review the interplay of iron overload, ineffective erythropoiesis, hepcidin and erythroferrone in beta thalassaemia including new findings obtained from the study of beta thalassaemic mice.
- Discuss the suggested role of circulating apo-transferrin and transferrin receptor TfR1 in counteracting ineffective erythropoiesis and hepcidin repression, leading to potential novel therapeutic approaches.
- (2) To review how our recently-improved understanding of iron toxicity informs strategies for iron chelation therapy before and after bone-marrow transplantation, but also becoming aware of how impending diagnostic advances could require a modification of these strategies in the near future.
- (3) Discuss recent findings on the pathophysiology of Diamond-Blackfan anaemia.
Learning Objectives of the presentation
After viewing this presentation the participant will be able to:
- DBA is a congenital erythroblastopenia amongst the inherited bone marrow failure syndromes (IBMFS), highly heterogenous in phenotype and genotype.
- DBA is the first ribosomopathy described and p53 stabilization is involved in DBA erythroblastopenia.
- HSP70 is one of the major key factors involved in DBA pathophysiology.
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