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Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

Wilkes, M. C. ; Siva, K. LU ; Chen, J. LU ; Varetti, G. ; Youn, M. Y. ; Chae, H. ; Ek, F. LU ; Olsson, R. LU orcid ; Lundbäck, T. and Dever, D. P. , et al. (2020) In Nature Communications 11(1).
Abstract

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient... (More)

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
issue
1
article number
3344
publisher
Nature Publishing Group
external identifiers
  • scopus:85087416409
  • pmid:32620751
ISSN
2041-1723
DOI
10.1038/s41467-020-17100-z
language
English
LU publication?
yes
id
c864a862-cd2b-4154-9e9d-df87e61abacd
date added to LUP
2020-07-14 11:22:31
date last changed
2024-06-26 18:54:21
@article{c864a862-cd2b-4154-9e9d-df87e61abacd,
  abstract     = {{<p>Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.</p>}},
  author       = {{Wilkes, M. C. and Siva, K. and Chen, J. and Varetti, G. and Youn, M. Y. and Chae, H. and Ek, F. and Olsson, R. and Lundbäck, T. and Dever, D. P. and Nishimura, T. and Narla, A. and Glader, B. and Nakauchi, H. and Porteus, M. H. and Repellin, C. E. and Gazda, H. T. and Lin, S. and Serrano, M. and Flygare, J. and Sakamoto, K. M.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-17100-z}},
  doi          = {{10.1038/s41467-020-17100-z}},
  volume       = {{11}},
  year         = {{2020}},
}