Blockade of miR-150 maturation by MLL-fusion/MYC/LIN-28 is required for MLL-associated leukemia Journal Article

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Authors: Jiang, X; Huang, H; Li, Z; Li, Y; Wang, X; Gurbuxani, S.; Chen, P; He, C; You, D.; Zhang, S; Wang, J; Arnovitz, S; Elkahloun, A; Price, C.; Hong, G. M.; Ren, H.; Kunjamma, R. B.; Neilly, M. B.; Matthews, J. M.; Xu, M; Larson, R. A.; Le Beau, M. M.; Slany, R. K.; Liu, P. P.; Lu, J; Zhang, J; Chen, J
Article Title: Blockade of miR-150 maturation by MLL-fusion/MYC/LIN-28 is required for MLL-associated leukemia
Abstract: 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 dash, verticalmiR-150 dash, verticalFLT3/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.
Journal Title: Cancer cell
Volume: 22
Issue: 4
ISSN: 1878-3686; 1535-6108
Publisher: Elsevier Inc  
Journal Place: United States
Date Published: 2012
Start Page: 524
End Page: 535
Language: eng
DOI/URL:

10.1016/j.ccr.2012.08.028

10.1016/j.ccr.2012.08.028
Notes: LR: 20130416; CI: Copyright (c) 2012; GEO/GSE30258; GEO/GSE34184; GEO/GSE34185; GR: P01 CA40046/CA/NCI NIH HHS/United States; GR: P30 CA014599/CA/NCI NIH HHS/United States; GR: R01 CA127277/CA/NCI NIH HHS/United States; GR: R01 CA127277/CA/NCI NIH HHS/United States; GR: R01 HL95896/HL/NHLBI NIH HHS/United States; JID: 101130617; 0 (Homeodomain Proteins); 0 (LIN-28 protein, human); 0 (MIRN150 microRNA, human); 0 (MLL protein, human); 0 (MYC protein, human); 0 (MicroRNAs); 0 (Mllt3 protein, mouse); 0 (Neoplasm Proteins); 0 (Nuclear Proteins); 0 (Proto-Oncogene Proteins c-myc); 0 (RNA-Binding Proteins); 0 (homeobox protein HOXA9); 0 (myeloid ecotropic viral integration site 1 protein); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); EC 2.7.10.1 (FLT3 protein, human); EC 2.7.10.1 (fms-Like Tyrosine Kinase 3); NIHMS407701; OID: NLM: NIHMS407701 [Available on 10/16/13]; OID: NLM: PMC3480215 [Available on 10/16/13]; PMCR: 2013/10/16 00:00; 2012/02/23 [received]; 2012/06/21 [revised]; 2012/08/30 [accepted]; ppublish