miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia

Nat Commun. 2016 Apr 26;7:11452. doi: 10.1038/ncomms11452.

Abstract

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.

Publication types

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

MeSH terms

  • Acute Disease
  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Down-Regulation
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Genes, Tumor Suppressor*
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / pathology
  • Mice, Inbred C57BL
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • MicroRNAs / therapeutic use
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / pathology
  • Signal Transduction / genetics

Substances

  • MIRN22 microRNA, human
  • MicroRNAs