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Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia

Sjögren, Sara E. LU ; Chen, Jun LU ; Mattebo, Alexander LU ; Alattar, Abdul G. LU orcid ; Karlsson, Helena LU ; Siva, Kavitha LU ; Soneji, Shamit LU ; Tedgård, Ulf LU ; Chen, Jane Jane and Gram, Magnus LU orcid , et al. (2022) In Experimental Hematology 105. p.50-61
Abstract

Diamond-Blackfan anemia (DBA) is a rare genetic disorder in which patients present a scarcity of erythroid precursors in an otherwise normocellular bone marrow. Most, but not all, patients carry mutations in ribosomal proteins such as RPS19, suggesting that compromised mRNA translation and ribosomal stress are pathogenic mechanisms causing depletion of erythroid precursors. To gain further insight to disease mechanisms in DBA, we performed a custom short hairpin RNA (shRNA) based screen against 750 genes hypothesized to affect DBA pathophysiology. Among the hits were two shRNAs against the erythroid specific heme-regulated eIF2α kinase (HRI), which is a negative regulator of mRNA translation. This study shows that shRNA-mediated HRI... (More)

Diamond-Blackfan anemia (DBA) is a rare genetic disorder in which patients present a scarcity of erythroid precursors in an otherwise normocellular bone marrow. Most, but not all, patients carry mutations in ribosomal proteins such as RPS19, suggesting that compromised mRNA translation and ribosomal stress are pathogenic mechanisms causing depletion of erythroid precursors. To gain further insight to disease mechanisms in DBA, we performed a custom short hairpin RNA (shRNA) based screen against 750 genes hypothesized to affect DBA pathophysiology. Among the hits were two shRNAs against the erythroid specific heme-regulated eIF2α kinase (HRI), which is a negative regulator of mRNA translation. This study shows that shRNA-mediated HRI silencing or loss of one HRI allele improves expansion of Rps19-deficient erythroid precursors, as well as improves the anemic phenotype in Rps19-deficient animals. We found that Rps19-deficient erythroblasts have elevated levels of unbound intracellular heme, which is normalized by HRI heterozygosity. Additionally, targeting elevated heme levels by treating cells with the heme scavenger alpha-1-microglobulin (A1M), increased proliferation of Rps19-deficient erythroid precursors and decreased heme levels in a disease-specific manner. HRI heterozygosity, but not A1M treatment, also decreased the elevated p53 activity observed in Rps19-deficient cells, indicating that p53 activation is caused by ribosomal stress and aberrant mRNA translation and not heme overload in Rps19-deficiency. Together, these findings suggest that targeting elevated heme levels is a promising new treatment strategy for DBA.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
105
pages
50 - 61
publisher
Elsevier
external identifiers
  • scopus:85120329576
  • pmid:34757171
ISSN
0301-472X
DOI
10.1016/j.exphem.2021.10.005
language
English
LU publication?
yes
id
cebfab3e-eb07-4898-b5b5-2e8d496e56e6
date added to LUP
2021-12-14 11:26:51
date last changed
2024-04-20 17:41:43
@article{cebfab3e-eb07-4898-b5b5-2e8d496e56e6,
  abstract     = {{<p>Diamond-Blackfan anemia (DBA) is a rare genetic disorder in which patients present a scarcity of erythroid precursors in an otherwise normocellular bone marrow. Most, but not all, patients carry mutations in ribosomal proteins such as RPS19, suggesting that compromised mRNA translation and ribosomal stress are pathogenic mechanisms causing depletion of erythroid precursors. To gain further insight to disease mechanisms in DBA, we performed a custom short hairpin RNA (shRNA) based screen against 750 genes hypothesized to affect DBA pathophysiology. Among the hits were two shRNAs against the erythroid specific heme-regulated eIF2α kinase (HRI), which is a negative regulator of mRNA translation. This study shows that shRNA-mediated HRI silencing or loss of one HRI allele improves expansion of Rps19-deficient erythroid precursors, as well as improves the anemic phenotype in Rps19-deficient animals. We found that Rps19-deficient erythroblasts have elevated levels of unbound intracellular heme, which is normalized by HRI heterozygosity. Additionally, targeting elevated heme levels by treating cells with the heme scavenger alpha-1-microglobulin (A1M), increased proliferation of Rps19-deficient erythroid precursors and decreased heme levels in a disease-specific manner. HRI heterozygosity, but not A1M treatment, also decreased the elevated p53 activity observed in Rps19-deficient cells, indicating that p53 activation is caused by ribosomal stress and aberrant mRNA translation and not heme overload in Rps19-deficiency. Together, these findings suggest that targeting elevated heme levels is a promising new treatment strategy for DBA.</p>}},
  author       = {{Sjögren, Sara E. and Chen, Jun and Mattebo, Alexander and Alattar, Abdul G. and Karlsson, Helena and Siva, Kavitha and Soneji, Shamit and Tedgård, Ulf and Chen, Jane Jane and Gram, Magnus and Flygare, Johan}},
  issn         = {{0301-472X}},
  language     = {{eng}},
  pages        = {{50--61}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Hematology}},
  title        = {{Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia}},
  url          = {{http://dx.doi.org/10.1016/j.exphem.2021.10.005}},
  doi          = {{10.1016/j.exphem.2021.10.005}},
  volume       = {{105}},
  year         = {{2022}},
}