MicroRNA-9 plays a role in interleukin-10-mediated expression of E-cadherin in acute myelogenous leukemia cells.

We previously showed that the CD82/signal transducer and activator of transcription/interleukin-10 (IL-10) axis is activated in CD34(+) /CD38(-) AML cells that favor the bone marrow microenvironment. The present study explored the novel biological function of IL-10 in regulation of expression of adhesion molecules in AML cells and found that exposing AML cells to IL-10 induced expression of E-cadherin, but not other adhesion molecules, including VLA4, CD29, and LFA1. Downregulation of E-cadherin with an siRNA suppressed the adhesion of leukemia cells to bone marrow-derived mesenchymal stem cells and enhanced the anti-leukemia effect of cytarabine. A microRNA (miRNA) database search identified an miR-9 as a candidate miRNA binding onto the 3'-UTR of E-cadherin and regulating its expression. Notably, treatment of leukemia cells with IL-10 decreased miR-9 expression through hypermethylation of the miR-9 CpG islands. In addition, downregulation of DNA methyltransferase 3A by siRNAs decreased E-cadherin expression in parallel with an increase in levels of miR-9 in leukemia cells. Notably, short hairpin RNA-mediated IL-10 downregulation impaired engraftment of human AML cells and enhanced the anti-leukemia effect of cytarabine in conjunction with miR-9 upregulation and E-cadherin downregulation in a human AML xenograft model. Taken together, the IL-10/E-cadherin axis may be a promising therapeutic target for treating AML.