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Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a

Wilkes, Mark C. ; Siva, Kavitha LU ; Varetti, Gianluca ; Mercado, Jacqueline ; Wentworth, Ethan P. ; Perez, Cristina A. ; Saxena, Mallika ; Kam, Sharon ; Kapur, Simryn and Chen, Jun LU , et al. (2020) In Experimental Hematology 91. p.65-77
Abstract

Diamond–Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK... (More)

Diamond–Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3′ untranslated region (3′UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.

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type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
91
pages
13 pages
publisher
Elsevier
external identifiers
  • scopus:85091607173
  • pmid:32926965
ISSN
0301-472X
DOI
10.1016/j.exphem.2020.09.187
language
English
LU publication?
yes
id
bd4107fc-387f-4fac-b87f-65f4e5da92fb
date added to LUP
2020-11-20 13:37:32
date last changed
2024-05-01 20:50:59
@article{bd4107fc-387f-4fac-b87f-65f4e5da92fb,
  abstract     = {{<p>Diamond–Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3′ untranslated region (3′UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.</p>}},
  author       = {{Wilkes, Mark C. and Siva, Kavitha and Varetti, Gianluca and Mercado, Jacqueline and Wentworth, Ethan P. and Perez, Cristina A. and Saxena, Mallika and Kam, Sharon and Kapur, Simryn and Chen, Jun and Narla, Anu and Glader, Bert and Lin, Shou and Serrano, Manuel and Flygare, Johan and Sakamoto, Kathleen M.}},
  issn         = {{0301-472X}},
  language     = {{eng}},
  month        = {{11}},
  pages        = {{65--77}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Hematology}},
  title        = {{Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond–Blackfan anemia through induction of miR-26a}},
  url          = {{http://dx.doi.org/10.1016/j.exphem.2020.09.187}},
  doi          = {{10.1016/j.exphem.2020.09.187}},
  volume       = {{91}},
  year         = {{2020}},
}