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

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.

• Authors: Mark C Wilkes, Kavitha Siva, Gianluca Varetti, Jacqueline Mercado, Ethan P Wentworth, Cristina A Perez, Mallika Saxena, Sharon Kam, Simryn Kapur, Jun Chen, Anu Narla, Bert Glader, Shou Lin, Manuel Serrano, Johan Flygare, Kathleen M Sakamoto
• Journal: Experimental hematology (Exp Hematol) Vol. 91 Pg. 65-77 (11 2020) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 32926965 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• Hematinics
• MIRN26A microRNA, human
• MicroRNAs
• Mirn26 microRNA, mouse
• Mirn26 microRNA, zebrafish
• RNA, Small Interfering
• Recombinant Proteins
• Metformin
• NLK protein, human
• Nlk protein, mouse
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• nemo-like kinase, zebrafish

Topics

• 3' Untranslated Regions (genetics)
• Anemia, Diamond-Blackfan (drug therapy, genetics)
• Animals
• Cells, Cultured
• Colony-Forming Units Assay
• Disease Models, Animal
• Erythropoiesis (drug effects, genetics)
• Gene Expression Regulation (drug effects)
• Genes, Reporter
• Hematinics (pharmacology, therapeutic use)
• Humans
• Metformin (pharmacology, therapeutic use)
• MicroRNAs (biosynthesis, genetics)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• RNA Stability
• RNA, Small Interfering (pharmacology)
• Recombinant Proteins (metabolism)
• Species Specificity
• Up-Regulation (drug effects)
• Zebrafish