LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas

Blood. 2012 Aug 23;120(8):1678-86. doi: 10.1182/blood-2012-02-410647. Epub 2012 Jul 13.

Abstract

miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155-based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti-miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti-miR-155 delivered systemically showed uptake in the BM CD19(+) cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155-knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti-miR-155-mediated inhibition of miR-155 in the treatment of WM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Female
  • Gene Silencing
  • Genetic Therapy
  • Humans
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / therapy
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / genetics*
  • Oligonucleotides / genetics
  • Oligonucleotides / therapeutic use*
  • Oligonucleotides, Antisense / genetics
  • Oligonucleotides, Antisense / therapeutic use*
  • Tumor Cells, Cultured
  • Waldenstrom Macroglobulinemia / genetics*
  • Waldenstrom Macroglobulinemia / pathology
  • Waldenstrom Macroglobulinemia / therapy

Substances

  • MIRN155 microRNA, human
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • locked nucleic acid