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

Xi Jiang, Hao Huang, Zejuan Li, Yuanyuan Li, Xiao Wang, Sandeep Gurbuxani, Ping Chen, Chunjiang He, Dewen You, Shuodan Zhang, Jinhua Wang, Stephen Arnovitz, Abdel Elkahloun, Colles Price, Gia Ming Hong, Haomin Ren, Rejani B. Kunjamma, Mary Beth Neilly, Jonathan M. Matthews, Mengyi XuRichard A. Larson, Michelle M. Le Beau, Robert K. Slany, Paul P. Liu, Jun Lu, Jiwang Zhang, Chuan He, Jianjun Chen*

*Corresponding author for this work

Research output: Contribution to journalArticle

114 Scopus citations

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⊣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.

Original languageEnglish (US)
Pages (from-to)524-535
Number of pages12
JournalCancer Cell
Volume22
Issue number4
DOIs
StatePublished - Oct 16 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    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., ... Chen, J. (2012). Blockade of miR-150 Maturation by MLL-Fusion/MYC/LIN-28 Is Required for MLL-Associated Leukemia. Cancer Cell, 22(4), 524-535. https://doi.org/10.1016/j.ccr.2012.08.028