A critical role of epigenetic inactivation of miR-9 in EVI1high pediatric AML

Nupur Mittal,Yue Sheng,Liping Li,Tongyu Zhu,Zhijian Qian,Xiaohong Qiao,Chao Hu,Fuxing Li

doi:10.1186/s12943-019-0952-z

Abstract

Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10–25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens. Here we report that EVI1 upregulation is associated with methylation of the miR-9 promoter and correlated with downregulation of miR-9 in human AML cell lines and bone marrow (BM) cells from pediatric patients. Reactivation of miR-9 by hypomethylating agents and forced expression of miR-9 in EVI1high leukemia cell lines and primary leukemia cells results in apoptosis and decreased proliferation of EVI1high leukemia cells. Furthermore, re-expression of miR-9 delays disease progression in EVI1high leukemia-xenograft mice. Our results suggest that EVI1-induced hypermethylation and downregulation of the miR-9 plays an important role in leukemogenesis in EVI-1high pediatric AML, indicating that hypomethylating agents may be a potential therapeutic strategy for EVI1high pediatric AML.

Highlights

Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10–25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens
We provide the first evidence, that miR-9 is significantly downregulated in a subset of pediatric AML patients with high expression of EVI1 and that miR-9 has a critical role in EVI1-induced leukemogenesis in pediatric patients, thereby establishing the role of miR-9 as a tumor suppressor in the pathogenesis of EVI1-induced myeloid leukemia
EVI1 regulates Runx1-mediated transcription activity [9] while miR-9 downregulation is associated with presence of RUNX1-ETO fusion gene in AML patients [6]

Summary

Introduction

Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10–25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens. To ascertain the effect of this EVI1 mediated hypermethylation on miR-9, we analyzed miR-9 expression by RT-qPCR in these cell lines after 48-h treatment of 5-AZA (Decitabine), which is a Mittal et al Molecular Cancer (2019) 18:30 Reactivation of miR-9 inhibits leukemic potential of EVI1 high leukemia cell lines and primary AML cells from EVI1high AML patients

Results

Conclusion