Metformin-induced suppression of NLK improves erythropoiesis in pre-clinical models of Diamond Blackfan Anemia through induction of miR-26a

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, or suppression of NLK expression, both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes mellitus with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data shows that the effects of metformin on erythroid proliferation and differentiation is mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3'UTR to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treat DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.