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

miR-22 suppresses DNA ligase III addiction in multiple myeloma.

Author information

1
Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy.
2
Pathology Unit, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
3
Department of Oncology and Hemato-oncology, University of Milan, and Hematology, Fondazione Cà Granda IRCCS Policlinico, Milan, Italy.
4
Department of Experimental and Clinical Medicine, Magna Græcia University, Campus Salvatore Venuta, Catanzaro, Italy. tassone@unicz.it.
5
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA. tassone@unicz.it.

Abstract

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.

PMID:
30120376
PMCID:
PMC6365379
DOI:
10.1038/s41375-018-0238-2
[Indexed for MEDLINE]
Free PMC Article

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