Multiple myeloma, gammopathies

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


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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  1. 1.

    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  Google Scholar 

  2. 2.

    Ntziachristos P, Abdel-Wahab O, Aifantis I. Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol. 2016;17:1016–24.

    CAS  Article  Google Scholar 

  3. 3.

    Evans JR, Feng FY, Chinnaiyan AM. The bright side of dark matter: lncRNAs in cancer. J Clin Invest. 2016;126:2775–82.

    Article  Google Scholar 

  4. 4.

    Ronchetti D, Agnelli L, Taiana E, Galletti S, Manzoni M, Todoerti K, et al. Distinct lncRNA transcriptional fingerprints characterize progressive stages of multiple myeloma. Oncotarget. 2016;7:14814–30.

    Article  Google Scholar 

  5. 5.

    Wong KY, Li Z, Zhang X, Leung GK, Chan GC, Chim CS. Epigenetic silencing of a long non-coding RNA KIAA0495 in multiple myeloma. Mol Cancer. 2015;14:175.

    Article  Google Scholar 

  6. 6.

    Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, et al. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 2011;6:1984–92.

    Article  Google Scholar 

  7. 7.

    Kato L, Begum NA, Burroughs AM, Doi T, Kawai J, Daub CO, et al. Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes. Proc Natl Acad Sci USA. 2012;109:2479–84.

    CAS  Article  Google Scholar 

  8. 8.

    Chaudhry MA. Expression pattern of small nucleolar RNA host genes and long non-coding RNA in X-rays-treated lymphoblastoid cells. Int J Mol Sci. 2013;14:9099–110.

    Article  Google Scholar 

  9. 9.

    Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72.

    CAS  Article  Google Scholar 

  10. 10.

    Ren S, Liu Y, Xu W, Sun Y, Lu J, Wang F, et al. Long noncoding RNA MALAT-1 is a new potential therapeutic target for castration resistant prostate cancer. J Urol. 2013;190:2278–87.

    CAS  Article  Google Scholar 

  11. 11.

    West JA, Davis CP, Sunwoo H, Simon MD, Sadreyev RI, Wang PI, et al. The long noncoding RNAs NEAT1 and MALAT1 bind active chromatin sites. Mol Cell. 2014;55:791–802.

    CAS  Article  Google Scholar 

  12. 12.

    Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–41.

    Article  Google Scholar 

  13. 13.

    Luo JH, Ren B, Keryanov S, Tseng GC, Rao UN, Monga SP, et al. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology. 2006;44:1012–24.

    CAS  Article  Google Scholar 

  14. 14.

    Guffanti A, Iacono M, Pelucchi P, Kim N, Solda G, Croft LJ, et al. A transcriptional sketch of a primary human breast cancer by 454 deep sequencing. BMC Genomics. 2009;10:163.

    Article  Google Scholar 

  15. 15.

    Cho SF, Chang YC, Chang CS, Lin SF, Liu YC, Hsiao HH, et al. MALAT1 long non-coding RNA is overexpressed in multiple myeloma and may serve as a marker to predict disease progression. BMC Cancer. 2014;14:809.

    Article  Google Scholar 

  16. 16.

    Handa H, Kuroda Y, Kimura K, Masuda Y, Hattori H, Alkebsi L, et al. Long non-coding RNA MALAT1 is an inducible stress response gene associated with extramedullary spread and poor prognosis of multiple myeloma. Br J Haematol. 2017;179:449–60.

    CAS  Article  Google Scholar 

  17. 17.

    Bennardo N, Cheng A, Huang N, Stark JM. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet. 2008;4:e1000110.

    Article  Google Scholar 

  18. 18.

    Pierce AJ, Johnson RD, Thompson LH, Jasin M. XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 1999;13:2633–8.

    CAS  Article  Google Scholar 

  19. 19.

    Zhan F, Barlogie B, Arzoumanian V, Huang Y, Williams DR, Hollmig K, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood. 2007;109:1692–1700.

    CAS  Article  Google Scholar 

  20. 20.

    Gutierrez NC, Sarasquete ME, Misiewicz-Krzeminska I, Delgado M, De Las Rivas J, Ticona FV, et al. Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling. Leukemia. 2010;24:629–37.

    CAS  Article  Google Scholar 

  21. 21.

    Lopez-Corral L, Corchete LA, Sarasquete ME, Mateos MV, Garcia-Sanz R, Ferminan E, et al. Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies. Haematologica. 2014;99:1365–72.

    CAS  Article  Google Scholar 

  22. 22.

    Huambachano O, Herrera F, Rancourt A, Satoh MS. Double-stranded DNA binding domain of poly(ADP-ribose) polymerase-1 and molecular insight into the regulation of its activity. J Biol Chem. 2011;286:7149–60.

    CAS  Article  Google Scholar 

  23. 23.

    Leppard JB, Dong Z, Mackey ZB, Tomkinson AE. Physical and functional interaction between DNA ligase IIIalpha and poly(ADP-Ribose) polymerase 1 in DNA single-strand break repair. Mol Cell Biol. 2003;23:5919–27.

    CAS  Article  Google Scholar 

  24. 24.

    Chiruvella KK, Liang Z, Wilson TE. Repair of double-strand breaks by end joining. Cold Spring Harb Perspect Biol. 2013;5:a012757.

    Article  Google Scholar 

  25. 25.

    Lennox KA, Behlke MA. Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res. 2016;44:863–77.

    CAS  Article  Google Scholar 

  26. 26.

    Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares AH, Smulson ME. Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis. J Biol Chem. 1998;273:13703–12.

    CAS  Article  Google Scholar 

  27. 27.

    Neri P, Ren L, Gratton K, Stebner E, Johnson J, Klimowicz A, et al. Bortezomib-induced “BRCAness” sensitizes multiple myeloma cells to PARP inhibitors. Blood. 2011;118:6368–79.

    CAS  Article  Google Scholar 

  28. 28.

    Jiang X, Wang G, Liu R, Wang Y, Wang Y, Qiu X, et al. RNase non-sensitive and endocytosis independent siRNA delivery system: delivery of siRNA into tumor cells and high efficiency induction of apoptosis. Nanoscale. 2013;5:7256–64.

    CAS  Article  Google Scholar 

  29. 29.

    Murakami T, Sawada H, Tamura G, Yudasaka M, Iijima S, Tsuchida K. Water-dispersed single-wall carbon nanohorns as drug carriers for local cancer chemotherapy. Nanomedicine (London). 2008;3:453–63.

    CAS  Article  Google Scholar 

  30. 30.

    Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC. Homology and enzymatic requirements of microhomology-dependent alternative end joining. Cell Death Dis. 2015;6:e1697.

    CAS  Article  Google Scholar 

  31. 31.

    Herrero AB, San Miguel J, Gutierrez NC. Deregulation of DNA double-strand break repair in multiple myeloma: implications for genome stability. PLoS ONE. 2015;10:e0121581.

    Article  Google Scholar 

  32. 32.

    Sallmyr A, Tomkinson AE, Rassool FV. Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. Blood. 2008;112:1413–23.

    CAS  Article  Google Scholar 

  33. 33.

    Tobin LA, Robert C, Nagaria P, Chumsri S, Twaddell W, Ioffe OB, et al. Targeting abnormal DNA repair in therapy-resistant breast cancers. Mol Cancer Res. 2012;10:96–107.

    CAS  Article  Google Scholar 

  34. 34.

    Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, et al. c-MYC generates repair errors via increased transcription of alternative-NHEJ factors, LIG3 and PARP1, in tyrosine kinase-activated leukemias. Mol Cancer Res. 2015;13:699–712.

    CAS  Article  Google Scholar 

  35. 35.

    Soni A, Siemann M, Grabos M, Murmann T, Pantelias GE, Iliakis G. Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining. Nucleic Acids Res. 2014;42:6380–92.

    CAS  Article  Google Scholar 

  36. 36.

    Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21:4257–61.

    CAS  Article  Google Scholar 

  37. 37.

    Balasubramaniam S, Beaver JA, Horton S, Fernandes LL, Tang S, Horne HN, et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer. Clin Cancer Res. 2017;23:7165–70.

    CAS  Article  Google Scholar 

  38. 38.

    Scott LJ. Niraparib: first global approval. Drugs. 2017;77:1029–34.

    Article  Google Scholar 

  39. 39.

    Aartsma-Rus A. FDA approval of nusinersen for spinal muscular atrophy makes 2016 the year of splice modulating oligonucleotides. Nucleic Acid Ther. 2017;27:67–69.

    CAS  Article  Google Scholar 

  40. 40.

    Smith RJ, Hiatt WR. Two new drugs for homozygous familial hypercholesterolemia: managing benefits and risks in a rare disorder. JAMA Intern Med. 2013;173:1491–2.

    CAS  Article  Google Scholar 

  41. 41.

    Highleyman L FDA approves fomivirsen, famciclovir, and Thalidomide. Food and Drug Administration. BETA 1998: 5.

  42. 42.

    Nelson SF, Miceli MC. FDA approval of eteplirsen for muscular dystrophy. JAMA. 2017;317:1480.

    Article  Google Scholar 

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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.


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).

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