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

详细信息    查看全文

• 作者：Lin Fu ; Jinlong Shi ; Anqi Liu ; Lei Zhou ; Mengmeng Jiang ; Huaping Fu ; Keman Xu ; Dandan Li ; Ailing Deng ; Qingyi Zhang ; Yifan Pang ; Yujie Guo ; Kai Hu ; Jiansuo Zhou ; Yapeng Wang ; Wenrong Huang ; Yu Jing ; Liping Dou ; Lili Wang ; Kailin Xu ; Xiaoyan Ke ; Clara Nervi ; Yonghui Li and Li Yu
• 刊名：International Journal of Cancer
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：140
• 期：3
• 页码：653-661
• 全文大小：540K
• ISSN：1097-0215

文摘

MicroRNA-9-1(m>miR-9-1m>) plays an important role in the mechanism that regulates the lineage fate of differentiating hematopoietic cells. Recent studies have shown that m>miR-9-1m> is downregulated in t (8; 21) AML. However, the pathogenic mechanisms underlying m>miR-9-1m> downregulation and the m>RUNX1-RUNX1T1m> fusion protein, generated from the translocation of t (8; 21) in AML, remain unclear. m>RUNX1-RUNX1T1m> can induce leukemogenesis through resides in and functions as a stable m>RUNX1-RUNX1T1m>-containing transcription factor complex. In this study, we demonstrate that m>miR-9-1m> expression increases significantly after the treatment of m>RUNX1-RUNX1T1m> (+) AML cell lines with decitabine (a DNMT inhibitor) and trichostatin A (an HDAC inhibitor). In addition, we show that m>RUNX1-RUNX1T1m> triggers the heterochromatic silencing of m>miR-9-1m> by binding to RUNX1-binding sites in the promoter region of m>miR-9-1m> and recruiting chromatin-remodeling enzymes, DNMTs, and HDACs, contributing to hypermethylation of m>miR-9-1m> in t (8; 21) AML. Furthermore, because m>RUNX1m>, m>RUNX1T1m>, and m>RUNX1-RUNX1T1m> are all regulated by m>miR-9-1m>, the silencing of m>miR-9-1m> enhances the oncogenic activity of these genes. Besides, overexpression of m>miR-9-1m> induces differentiation and inhibits proliferation in t (8; 21) AML cell lines. In conclusion, our results indicate a feedback circuitry involving m>miR-9-1m> and m>RUNX1-RUNX1T1m>, contributing to leukemogenesis in m>RUNX1-RUNX1T1m> (+) AML cell lines.