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

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• 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(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.