Multiple myeloma, gammopathies

Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma

Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA). Overexpression of MALAT1 has been demonstrated to related to poor prognosis of multiple myeloma (MM) patients. Here, we demonstrated that MALAT1 plays important roles in MM DNA repair and cell death. We found bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM express elevated MALAT1 and involve in alternative non-homozygous end joining (A-NHEJ) pathway by binding to PARP1 and LIG3, two key components of the A-NHEJ protein complex. Degradation of the MALAT1 RNA by RNase H using antisense gapmer DNA oligos in MM cells stimulated poly-ADP-ribosylation of nuclear proteins, defected the DNA repair pathway, and further provoked apoptotic pathways. Anti-MALAT1 therapy combined with PARP1 inhibitor or proteasome inhibitor in MM cells showed a synergistic effect in vitro. Furthermore, using novel single-wall carbon nanotube (SWCNT) conjugated with anti-MALAT1 oligos, we successfully knocked-down MALAT1 RNA in cultured MM cell lines and xenograft murine models. Most importantly, anti-MALAT1 therapy induced DNA damage and cell apoptosis in vivo, indicating that MALAT1 could serve as a potential novel therapeutic target for MM treatment.

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Acknowledgements

We thank the Lerner Research Institute proteomic, genomic and imaging cores for their assistance and support. We thank Dr. Cassandra Talerico, a salaried employee of the Cleveland Clinic, for editorial assistance and helpful comments.

Funding

This work was financially supported by NIH/NCI grant R00 CA172292 (to J.-J.Z.) and start-up funds (to J.-J.Z.) and the Clinical and Translational Science Collaborative (CTSC) of Case Western Reserve University Core Utilization Pilot Grant (to J.-J.Z.). The Orbitrap Elite instrument was purchased via an NIH shared instrument grant, 1S10RR031537-01. This work utilized the Leica SP8 confocal microscope that was purchased with funding from National Institutes of Health SIG grant 1S10OD019972-01.

Author contributions

Y.H. and J.L. designed and performed experiments, analyzed data, and wrote the manuscript; H.F., J.F., C.L., W.C., and G.Z. performed experiments and analyzed data; O.S., M.J., S.L., R.F., and Q.Y. provided clinical samples. J.-J.Z. designed the project, performed experiments, analyzed data, and wrote the manuscript.

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Correspondence to Jian-Jun Zhao.

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Hu, Y., Lin, J., Fang, H. et al. Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia 32, 2250–2262 (2018). https://doi.org/10.1038/s41375-018-0104-2

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