Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Multiple Myeloma, Gammopathies

MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib

Leukemia volume 29, pages 2347–2354 (2015)Cite this article

Subjects

Abstract

Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. In t(4;14) MM, the MM SET domain (MMSET) protein is universally overexpressed and has been suggested to have an important tumorigenic role. However, the exact molecular targets underlying MMSET activity are not well understood. Here, we found in t(4;14) MM cells that MMSET knockdown decreases interferon regulatory factor 4 (IRF4) expression, and ectopic MMSET increases IRF4 expression, suggesting that MMSET is an upstream regulator of IRF4. Further analyses indicated an interaction between MMSET and nuclear factor-κB, which both bind to the IRF4 promoter region. A luciferase reporter assay showed that MMSET is an important functional element for the IRF4 promoter. MMSET knockdown induces apoptosis and potentiates the effects of bortezomib in vitro and in vivo. Importantly, we found that bortezomib could reduce expression of MMSET and IRF4. This might partly explain the additive effect of combining MMSET knockdown and bortezomib treatment. These results identify MMSET as a key regulator involved in the regulatory network of transcription factor IRF4, which is critical for MM cell survival, suggesting that the combination of MMSET inhibition and bortezomib is likely to improve patient outcome in MM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Lauring J, Abukhdeir AM, Konishi H, Garay JP, Gustin JP, Wang Q et al. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 2008; 111: 856–864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bergsagel PL, Kuehl WM . Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005; 23: 6333–6338.

    Article  CAS  PubMed  Google Scholar 

  3. Bergsagel PL, Kuehl WM . Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma. Immunol Rev 2003; 194: 96–104.

    Article  CAS  PubMed  Google Scholar 

  4. Keats JJ, Reiman T, Belch AR, Pilarski LM . Ten years and counting: so what do we know about t(4;14)(p16;q32) multiple myeloma. Leuk Lymphoma 2006; 47: 2289–2300.

    Article  CAS  PubMed  Google Scholar 

  5. Keats JJ, Reiman T, Maxwell CA, Taylor BJ, Larratt LM, Mant MJ et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 2003; 101: 1520–1529.

    Article  CAS  PubMed  Google Scholar 

  6. Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy Jr J . A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. Blood 2003; 101: 2374–2376.

    Article  CAS  PubMed  Google Scholar 

  7. Keats JJ, Maxwell CA, Taylor BJ, Hendzel MJ, Chesi M, Bergsagel PL et al. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 2005; 105: 4060–4069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sun XJ, Wei J, Wu XY, Hu M, Wang L, Wang HH et al. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem 2005; 280: 35261–35271.

    Article  CAS  PubMed  Google Scholar 

  9. Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ, Sirulnik A et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 2008; 111: 3145–3154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kang HB, Choi Y, Lee JM, Choi KC, Kim HC, Yoo JY et al. The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS Lett 2009; 583: 1880–1886.

    Article  CAS  PubMed  Google Scholar 

  11. Kim JY, Kee HJ, Choe NW, Kim SM, Eom GH, Baek HJ et al. Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol Cell Biol 2008; 28: 2023–2034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li Y, Trojer P, Xu CF, Cheung P, Kuo A, Drury WJ et al. The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate. J Biol Chem 2009; 284: 34283–34295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 2009; 460: 287–291.

    Article  CAS  PubMed  Google Scholar 

  14. Pei H, Zhang L, Luo K, Qin Y, Chesi M, Fei F et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 2011; 470: 124–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell 2011; 44: 609–620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brito JL, Walker B, Jenner M, Dickens NJ, Brown NJ, Ross FM et al. MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells. Haematologica 2009; 94: 78–86.

    Article  CAS  PubMed  Google Scholar 

  17. Martinez-Garcia E, Popovic R, Min DJ, Sweet SM, Thomas PM, Zamdborg L et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 2011; 117: 211–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang Z, Wu H, Chuai S, Xu F, Yan F, Englund N et al. NSD2 is recruited through its PHD domain to oncogenic gene loci to drive multiple myeloma. Cancer Res 2013; 73: 6277–6288.

    Article  CAS  PubMed  Google Scholar 

  19. Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 2011; 118: 4771–4779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dib A, Gabrea A, Glebov OK, Bergsagel PL, Kuehl WM . Characterization of MYC translocations in multiple myeloma cell lines. J Natl Cancer Inst Monogr 2008; 39: 25–31.

    Article  CAS  Google Scholar 

  21. Xie Z, Gunaratne J, Cheong LL, Liu SC, Koh TL, Huang G et al. Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma. Oncotarget 2013; 4: 1008–1018.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Xie Z, Bi C, Cheong LL, Liu SC, Huang G, Zhou J et al. Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. PLoS One 2011; 6: e21583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kho PS, Wang Z, Zhuang L, Li Y, Chew JL, Ng HH et al. P53-regulated transcriptional program associated with genotoxic stress-induced apoptosis. J Biol Chem 2004; 279: 21183–21192.

    Article  CAS  PubMed  Google Scholar 

  24. Xie Z, Choong PF, Poon LF, Zhou J, Khng J, Jasinghe VJ et al. Inhibition of CD44 expression in hepatocellular carcinoma cells enhances apoptosis, chemosensitivity, and reduces tumorigenesis and invasion. Cancer Chemother Pharmacol 2008; 62: 949–957.

    Article  CAS  PubMed  Google Scholar 

  25. Ozvaran MK, Cao XX, Miller SD, Monia BA, Hong WK, Smythe WR . Antisense oligonucleotides directed at the bcl-xl gene product augment chemotherapy response in mesothelioma. Mol Cancer Ther 2004; 3: 545–550.

    CAS  PubMed  Google Scholar 

  26. Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12: 115–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shaffer AL, Emre NC, Lamy L, Ngo VN, Wright G, Xiao W et al. IRF4 addiction in multiple myeloma. Nature 2008; 454: 226–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lucio-Eterovic AK, Singh MM, Gardner JE, Veerappan CS, Rice JC, Carpenter PB . Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function. Proc Natl Acad Sci USA 2010; 107: 16952–16957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bannister AJ, Schneider R, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T . Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. J Biol Chem 2005; 280: 17732–17736.

    Article  CAS  PubMed  Google Scholar 

  30. Huang X, Di Liberto M, Jayabalan D, Liang J, Ely S, Bretz J et al. Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. Blood 2012; 120: 1095–1106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM . Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA 1996; 93: 13931–13936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL . The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 1998; 92: 3025–3034.

    CAS  PubMed  Google Scholar 

  33. Chang H, Sloan S, Li D, Zhuang L, Yi QL, Chen CI et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol 2004; 125: 64–68.

    PubMed  Google Scholar 

  34. Chng WJ, Glebov O, Bergsagel PL, Kuehl WM . Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol 2007; 20: 571–596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shaffer AL, Emre NC, Romesser PB, Staudt LM . IRF4: immunity. Malignancy! Therapy? Clin Cancer Res 2009; 15: 2954–2961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gualco G, Weiss LM, Bacchi CE . MUM1/IRF4: a review. Appl Immunohistochem Mol Morphol 2010; 18: 301–310.

    Article  CAS  PubMed  Google Scholar 

  37. Yang P, Guo L, Duan ZJ, Tepper CG, Xue L, Chen X et al. Histone methyltransferase NSD2/MMSET mediates constitutive NF-kappaB signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. Mol Cell Biol 2012; 32: 3121–3131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS et al. Regulation of p53 activity through lysine methylation. Nature 2004; 432: 353–360.

    Article  CAS  PubMed  Google Scholar 

  39. Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T et al. G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 2010; 285: 9636–9641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang X, Wen H, Shi X . Lysine methylation: beyond histones. Acta Biochim Biophys Sin 2012; 44: 14–27.

    Article  PubMed  Google Scholar 

  41. Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci USA 2010; 107: 46–51.

    Article  CAS  PubMed  Google Scholar 

  42. Lopez-Girona A, Heintel D, Zhang LH, Mendy D, Gaidarova S, Brady H et al. Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol 2011; 154: 325–336.

    Article  CAS  PubMed  Google Scholar 

  43. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 2009; 114: 1046–1052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bergsagel PL, Mateos MV, Gutierrez NC, Rajkumar SV, San Miguel JF . Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 2013; 121: 884–892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kalff A, Spencer A . The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies. Blood Cancer J 2012; 2: e89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc 2013; 88: 360–376.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Medical Research Council of Singapore Grant NMRC/BNIG/2006/2013 and the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative. WJC is supported by NMRC Clinician Scientist Investigator award.

Author contributions

ZX designed the research, performed the experiments and wrote the manuscript; CB performed gene expression microarray experiment; JYC, ZLC and NM helped with animal experiments; and WJC designed the research and wrote the manuscript.

Author information

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore

    Z Xie, C Bi, Z L Chan & W J Chng

  2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    J Y Chooi, N Mustafa & W J Chng

  3. Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore

    W J Chng

Authors
  1. Z Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Y Chooi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z L Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Mustafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W J Chng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W J Chng.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, Z., Bi, C., Chooi, J. et al. MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib. Leukemia 29, 2347–2354 (2015). https://doi.org/10.1038/leu.2015.169

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.169

This article is cited by

Search

Advanced search

Quick links