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Myeloid leukemia with high EVI1 expression is sensitive to 5-aza-2′-deoxycytidine by targeting miR-9

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Abstract

Purpose

High expression of ecotropic viral integration site 1 (EVI1) has been associated with a poor prognosis in leukemia patients, but the underlying mechanism remains unclear. Aberrant expression of microRNAs plays critical roles in leukemia development. MiR-9 is a putative potential target of EVI1. We have investigated the regulating mechanism of miR-9 by EVI1 in leukemia cells.

Methods

We first examined the relationship between miR-9 and EVI1 expression levels in nine leukemia cell lines by RT-PCR. Then we forced high expression of EVI1 in UoCM1 and K562 cells to confirm the downregulation of miR-9 by EVI1. Methylation of the miR-9 promoter region was detected by DNA bisulfite sequencing. We treated the EVI1-overexpressing cells with the hypomethylating agent 5-aza-2′-deoxycytidine (5-AZA) to reverse EVI1-induced hypermethylation of miR-9.

Results

EVI1 and miR-9 expression was negative related. Forced expression of EVI1 downregulated miR-9 by inducing hypermethylation of the miR-9 promoter. 5-AZA reversed high EVI1-induced hypermethylation of the miR-9 promoter and restored the expression of miR-9. 5-AZA induced extensive apoptosis and inhibited proliferation through cell cycle arrest in EVI1-overexpressing leukemia cells.

Conclusions

Our results suggest that EVI1 may be involved in leukemia cell proliferation and apoptosis via the regulation of miR-9 promoter methylation. 5-AZA may represent a promising therapeutic option for EVI1-high leukemia patients.

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Funding

This work was supported by Advanced Suitable Technology Popularization Project of Shanghai Health System (Grant no. 2013SY073).

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Authors and Affiliations

  1. Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, 200065, China

    F. Li, W. He, R. Geng & X. Xie

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  1. F. Li
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  2. W. He
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  3. R. Geng
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  4. X. Xie
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Correspondence to X. Xie.

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Li, F., He, W., Geng, R. et al. Myeloid leukemia with high EVI1 expression is sensitive to 5-aza-2′-deoxycytidine by targeting miR-9. Clin Transl Oncol 22, 137–143 (2020). https://doi.org/10.1007/s12094-019-02121-y

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  • DOI: https://doi.org/10.1007/s12094-019-02121-y

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