A critical role of epigenetic inactivation of miR-9 in EVI1 high pediatric AML

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 EVI1^high leukemia cell lines and primary leukemia cells results in apoptosis and decreased proliferation of EVI1^high leukemia cells. Furthermore, re-expression of miR-9 delays disease progression in EVI1^high leukemia-xenograft mice. Our results suggest that EVI1-induced hypermethylation and downregulation of the miR-9 plays an important role in leukemogenesis in EVI-1^high pediatric AML, indicating that hypomethylating agents may be a potential therapeutic strategy for EVI1^high pediatric AML.

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