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

Cancer Cell. 2012 Oct 16;22(4):524-35. doi: 10.1016/j.ccr.2012.08.028.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • DNA Methylation
  • Down-Regulation
  • 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
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Homeodomain Proteins
  • KMT2A protein, human
  • Lin28A protein, human
  • MEIS1 protein, human
  • MIRN150 microRNA, human
  • MYC protein, human
  • Meis1 protein, mouse
  • MicroRNAs
  • Mllt3 protein, mouse
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA-Binding Proteins
  • homeobox protein HOXA9
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3

Associated data

  • GEO/GSE30258
  • GEO/GSE34184
  • GEO/GSE34185