Eur Rev Med Pharmacol Sci 2017; 21 (4): 786-794

A minicircuitry comprised of microRNA-9 and SIRT1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

L. Zhou, L. Fu, N. Lv, X.-S. Chen, J. Liu, Y. Li, Q.-Y. Xu, S. Huang, X.-D. Zhang, L.-P. Dou, L.L. Wang, Y.-H. Li, L. Yu

Department of Hematology, Chinese PLA General Hospital, Beijing, China. chunhuiliyu@yahoo.com


OBJECTIVE: The AML1-ETO fusion protein (AE) resulting from the t(8;21) translocation is highly related to the pathogenesis and development of leukemia. microRNA-9 (miR-9) acts as a tumor suppressor gene in AE-positive acute myeloid leukemia (AML). Silent mating type information regulation 2 homolog-1 (SIRT1) is overexpressed in most cancer cells by increasing proliferation as a tumorigenic gene. The present study was performed to investigate the underlying interaction between miR-9 and SIRT1 in AE-positive AML.

PATIENTS AND METHODS: Expression of miR-9 and SIRT1 in AE-positive AML patients, healthy donors and AML cell lines were detected by qPCR. Relevance between miR-9 and SIRT1 was assessed by plasmid transfection, Western blot and correlation analysis. Luciferase assay was used to confirm the target gene of miR-9. Knockdown of SIRT1 in different cell lines was achieved by shRNA transfection and CCK-8 assay was used to investigate the effects on cell proliferation.

RESULTS: The miR-9 expression was lower in AE-positive cell lines compared to that in other AE-negative AML cell lines, while expression of SIRT1 was higher in AE-positive cell lines. Expression of miR-9 was also downregulated in adult primary t(8;21) AML patients compared to healthy donors. The over-expression of miR-9 decreased luciferase activity of wild-type SIRT1, which was recovered after transfection with mutant SIRT1. The miR-9 directly targets SIRT1 by binding to its 3′-untranslated region and reducing its protein levels. Importantly, miR-9 and SIRT1 mRNA levels were inversely correlated in AE-positive AML cell lines and t(8;21) AML primary leukemia cells. Knockdown of SIRT1 levels using shSIRT1 inhibited cell proliferation in AE-positive AML cell lines.

CONCLUSIONS: SIRT1 is the target gene of miR-9 and the signaling pathway connecting miR-9 and SIRT1 is a therapeutic target for t(8;21) AML.

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L. Zhou, L. Fu, N. Lv, X.-S. Chen, J. Liu, Y. Li, Q.-Y. Xu, S. Huang, X.-D. Zhang, L.-P. Dou, L.L. Wang, Y.-H. Li, L. Yu
A minicircuitry comprised of microRNA-9 and SIRT1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

Eur Rev Med Pharmacol Sci
Year: 2017
Vol. 21 - N. 4
Pages: 786-794