miR-22 suppresses DNA ligase III addiction in multiple myeloma

Leukemia. 2019 Feb;33(2):487-498. doi: 10.1038/s41375-018-0238-2. Epub 2018 Aug 17.


Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Proliferation
  • DNA Damage
  • DNA Ligase ATP / genetics
  • DNA Ligase ATP / metabolism*
  • DNA Repair
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MicroRNAs / genetics*
  • Multiple Myeloma / enzymology
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology*
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Prognosis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • MIRN22 microRNA, human
  • MicroRNAs
  • Poly-ADP-Ribose Binding Proteins
  • DNA Ligase ATP
  • LIG3 protein, human

Grant support