Blockade of miR-150 Maturation by MLL-Fusion/MYC/LIN-28 Is Required for MLL-Associated Leukemia

• Published in: Cancer cell Vol. 22; no. 4; pp. 524 - 535
• Main Authors: Jiang, Xi, Huang, Hao, Li, Zejuan, Li, Yuanyuan, Wang, Xiao, Gurbuxani, Sandeep, Chen, Ping, He, Chunjiang, You, Dewen, Zhang, Shuodan, Wang, Jinhua, Arnovitz, Stephen, Elkahloun, Abdel, Price, Colles, Hong, Gia-Ming, Ren, Haomin, Kunjamma, Rejani B., Neilly, Mary Beth, Matthews, Jonathan M., Xu, Mengyi, Larson, Richard A., Le Beau, Michelle M., Slany, Robert K., Liu, Paul P., Lu, Jun, Zhang, Jiwang, He, Chuan, Chen, Jianjun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.10.2012
• Subjects: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; DNA Methylation; Down-Regulation; fms-Like Tyrosine Kinase 3 - genetics; Gene Dosage; Gene Expression Regulation, Leukemic; Histone-Lysine N-Methyltransferase; Homeodomain Proteins - physiology; Humans; Leukemia - etiology; Mice; MicroRNAs - analysis; MicroRNAs - antagonists & inhibitors; MicroRNAs - physiology; Mutation; Myeloid Ecotropic Viral Integration Site 1 Protein; Myeloid-Lymphoid Leukemia Protein - physiology; Neoplasm Proteins - physiology; Nuclear Proteins - genetics; Proto-Oncogene Proteins c-myc - physiology; RNA-Binding Proteins - physiology; Signal Transduction
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2012.08.028

Expression of microRNAs (miRNAs) is under stringent regulation at both transcriptional and posttranscriptional levels. Disturbance at either level could cause dysregulation of miRNAs. Here, we show that MLL fusion proteins negatively regulate production of miR-150, an miRNA widely repressed in acute leukemia, by blocking miR-150 precursors from being processed to mature miRNAs through MYC/LIN28 functional axis. Forced expression of miR-150 dramatically inhibited leukemic cell growth and delayed MLL-fusion-mediated leukemogenesis, likely through targeting FLT3 and MYB and thereby interfering with the HOXA9/MEIS1/FLT3/MYB signaling network, which in turn caused downregulation of MYC/LIN28. Collectively, we revealed a MLL-fusion/MYC/LIN28⊣miR-150⊣FLT3/MYB/HOXA9/MEIS1 signaling circuit underlying the pathogenesis of leukemia, where miR-150 functions as a pivotal gatekeeper and its repression is required for leukemogenesis. ► miR-150 is downregulated in most cases of AML ► Maturation of miR-150 is inhibited by the MLL-fusion/MYC/LIN28 functional axis ► miR-150 inhibits MLL-associated leukemogenesis by downregulating FLT3 and MYB ► Discovery of a MLL-fusion/MYC/LIN28⊣miR-150⊣FLT3/MYB/HOXA9/MEIS1 signaling circuit