title: A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia.
abstract: 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.
authors: Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, 100191, China.|Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
authors: Lin
authors: L
authors: Fu
authors: Department of Biomedical Engineering, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Jinlong
authors: J
authors: Shi
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Anqi
authors: A
authors: Liu
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Lei
authors: L
authors: Zhou
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Mengmeng
authors: M
authors: Jiang
authors: Department of nuclear medicine, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Huaping
authors: H
authors: Fu
authors: College of medical laboratory science and technology, Harbin Medical University, Daqing, 163319, China.
authors: Keman
authors: K
authors: Xu
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Dandan
authors: D
authors: Li
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Ailing
authors: A
authors: Deng
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Qingyi
authors: Q
authors: Zhang
authors: Department of Medicine, William Beaumont Hospital, Royal Oak, MI, 48073.
authors: Yifan
authors: Y
authors: Pang
authors: College of Science, North China University of Technology, Beijing, 100144, China.
authors: Yujie
authors: Y
authors: Guo
authors: Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, 100191, China.
authors: Kai
authors: K
authors: Hu
authors: Department of clinical laboratory, Peking University, Third Hospital, Beijing, 100191, China.
authors: Jiansuo
authors: J
authors: Zhou
authors: Department of reproduction center, Peking University, Third Hospital, Beijing, 100191, China.
authors: Yapeng
authors: Y
authors: Wang
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Wenrong
authors: W
authors: Huang
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Yu
authors: Y
authors: Jing
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Liping
authors: L
authors: Dou
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Lili
authors: L
authors: Wang
authors: Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
authors: Kailin
authors: K
authors: Xu
authors: Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, 100191, China.
authors: Xiaoyan
authors: X
authors: Ke
authors: Department of Medico-Surgical Sciences and Biotechnologies, University of Rome "La Sapienza" Polo Pontino, Latina, 04100, Italy.
authors: Clara
authors: C
authors: Nervi
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Yonghui
authors: Y
authors: Li
authors: Department of Hematology, Chinese PLA General Hospital, Beijing, 100853, China.
authors: Li
authors: L
authors: Yu
mesh_terms: D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics; D020298:U937 Cells
chemical_list: D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors
keywords: 21); RUNX1-RUNX1T1; acute myeloid leukemia; miR-9-1; t (8