MiR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3

Yunyuan Zhang,Chunjie Yu,Zhijian Qian,Tongyu Zhu,Fuxing Li,Liping Li,Vitalyi Senyuk,John G Quigley

doi:10.1038/s41598-018-24628-0

Abstract

MicroRNAs (miRNAs) are emerging as critical regulators of normal and malignant hematopoiesis. In previous studies of acute myeloid leukemia miR-9 overexpression was commonly observed. Here, we show that ectopic expression of miR-9 in vitro and in vivo significantly blocks differentiation of erythroid progenitor cells with an increase in reactive oxygen species (ROS) production. Consistent with this observation, ROS scavenging enzymes, including superoxide dismutase (Sod2), Catalase (Cat), and glutathine peroxidase (Gpx1), are down-regulated by miR-9. In addition, miR-9 suppresses expression of the erythroid transcriptional regulator FoxO3, and its down-stream targets Btg1 and Cited 2 in erythroid progenitor cells, while expression of a constitutively active form of FoxO3 (FoxO3-3A) reverses miR-9-induced suppression of erythroid differentiation, and inhibits miR-9-induced ROS production. Thus, our findings indicate that aberrant expression of miR-9 blocks erythropoiesis by deregulating FoxO3-mediated pathways, which may contribute to the ineffective erythropoiesis observed in patients with hematological malignancies.

Highlights

Over the last decade it has become apparent that non-coding RNAs function as regulators of crucial cellular processes and play a critical role in human diseases[1]
We find that forced expression of miR-9 inhibits erythroid progenitor differentiation both in vitro and in vivo, FoxO3 is a critical regulator of erythropoiesis and is required for regulation of oxidative stress in erythroid progenitor cells[20,21]
We find that ectopic expression of miR-9 inhibits erythroid differentiation of G1ER cells and erythroid progenitor cells derived from murine fetal liver

Summary

Introduction

Over the last decade it has become apparent that non-coding RNAs function as regulators of crucial cellular processes and play a critical role in human diseases[1]. The upregulation of miR9 expression has been noted in various hematological malignancies, including Hodgkin’s lymphoma[11], AML12–14, ALL15 and MLL-AF9-induced leukemia[16] while it appears to be down-regulated in some cases of ALL17 and in pediatric AML with t(8;21)[18]. We find that forced expression of miR-9 inhibits erythroid progenitor differentiation both in vitro and in vivo, FoxO3 is a critical regulator of erythropoiesis and is required for regulation of oxidative stress in erythroid progenitor cells[20,21]. We observe that ectopic expression of miR-9 induces reactive oxygen species (ROS) production in erythroid progenitor cells and inhibits their differentiation through regulation of FoxO3 expression. Our findings suggest that a low level of miR-9 expression in erythroid progenitor cells is critical for maintenance of normal erythropoiesis

Methods

Results

Conclusion