A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia

MicroRNA-9-1(miR-9-1) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that miR-9-1 is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying miR-9-1 downregulation and the RUNX1-RUNX1T1 fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. RUNX1-RUNX1T1 can induce leukemogenesis through resides in and functions as a stable RUNX1-RUNX1T1-containing transcription factor complex. In this study, we demonstrate that miR-9-1 expression increases significantly after the treatment of RUNX1-RUNX1T1 (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that RUNX1-RUNX1T1 triggers the heterochromatic silencing of miR-9-1 by binding to RUNX1-binding sites in the promoter region of miR-9-1 and recruiting chromatin-remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of miR-9-1 in t (8; 21) AML. Furthermore, because RUNX1, RUNX1T1, and RUNX1-RUNX1T1 are all regulated by miR-9-1, the silencing of miR-9-1 enhances the oncogenic activity of these genes. Besides, overexpression of miR-9-1 induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving miR-9-1 and RUNX1-RUNX1T1, contributing to leukemogenesis in RUNX1-RUNX1T1 (+) AML cell lines. What's new? T (8;21), which is one of the most frequent chromosomal translocations in acute myeloid leukemia (AML), leads to the formation of the RUNX1-RUNX1T1 fusion transcription factor. The mechanisms underlying leukemogenesis however remain unclear. Here, the authors show that RUNX1-RUNX1T1 triggers the heterochromatic silencing of miR-9-1, contributing to hypermethylation of miR-9-1 promoter in t (8; 21) AML. miR-9-1 silencing promotes the expression of target genes, including RUNX1, RUNX1T1 and RUNX1-RUNX1T1, which prevents differentiation and promotes proliferation of t (8; 21) AML. The results indicate a feedback circuitry involving miR-9-1 and RUNX1-RUNX1T1 contributing to leukemogenesis in t (8; 21) AML cell lines.