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

Research output: Contribution to journalArticle

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.

Details

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
Organisations
External organisations
  • Stanford University
  • Spanish National Cancer Research Center (CNIO)
  • University of California, Los Angeles
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Other Basic Medicine
Original languageEnglish
Pages (from-to)65-77
Number of pages13
JournalExperimental Hematology
Volume91
Publication statusPublished - 2020 Nov 1
Publication categoryResearch
Peer-reviewedYes