PUBLICATION
Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond-Blackfan anemia through induction of miR-26a
- Authors
- Wilkes, M.C., Siva, K., Varetti, G., Mercado, J., Wentworth, E.P., Perez, C.A., Saxena, M., Kam, S., Kapur, S., Chen, J., Narla, A., Glader, B., Lin, S., Serrano, M., Flygare, J., Sakamoto, K.M.
- ID
- ZDB-PUB-201002-47
- Date
- 2020
- Source
- Experimental hematology 91: 65-77 (Journal)
- Registered Authors
- Lin, Shuo
- Keywords
- none
- MeSH Terms
-
- Metformin/pharmacology
- Metformin/therapeutic use*
- RNA Stability
- Mitogen-Activated Protein Kinases/antagonists & inhibitors*
- Up-Regulation/drug effects
- Cells, Cultured
- Erythropoiesis/drug effects*
- Erythropoiesis/genetics
- Protein Serine-Threonine Kinases/antagonists & inhibitors*
- Humans
- Zebrafish
- Anemia, Diamond-Blackfan/drug therapy*
- Anemia, Diamond-Blackfan/genetics
- RNA, Small Interfering/pharmacology
- Gene Expression Regulation/drug effects
- Recombinant Proteins/metabolism
- 3' Untranslated Regions/genetics
- Disease Models, Animal
- Species Specificity
- Genes, Reporter
- Colony-Forming Units Assay
- Animals
- Hematinics/pharmacology
- Hematinics/therapeutic use*
- MicroRNAs/biosynthesis*
- MicroRNAs/genetics
- PubMed
- 32926965 Full text @ Exp. Hematol.
Citation
Wilkes, M.C., Siva, K., Varetti, G., Mercado, J., Wentworth, E.P., Perez, C.A., Saxena, M., Kam, S., Kapur, S., Chen, J., Narla, A., Glader, B., Lin, S., Serrano, M., Flygare, J., Sakamoto, K.M. (2020) Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond-Blackfan anemia through induction of miR-26a. Experimental hematology. 91:65-77.
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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping