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:

Myeloma

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

Leukemia volume 26, pages 1073–1080 (2012)Cite this article

A Corrigendum to this article was published on 09 May 2012

Abstract

Bone morphogenetic proteins (BMPs) have been shown to induce apoptosis and growth arrest in myeloma cells. However, the molecular mechanisms behind these events are not known. The MYC oncogene is a master regulator of cell growth and protein synthesis and MYC overexpression has been proposed to be associated with the progression of multiple myeloma. Here, we show that BMP-induced apoptosis in myeloma cells is dependent on downregulation of MYC. Moreover, the results suggest that targeting the MYC addiction in multiple myeloma is an efficient way of killing a majority of primary myeloma clones. We also found that myeloma cells harboring immunoglobulin (IG)-MYC translocations evaded BMP-induced apoptosis, suggesting a novel way for myeloma cells to overcome potential tumor suppression by BMPs.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113: 5412–5417.

    Article  CAS  Google Scholar 

  2. Bergsagel PL, Kuehl WM . Chromosome translocations in multiple myeloma. Oncogene 2001; 20: 5611–5622.

    Article  CAS  Google Scholar 

  3. Anguiano A, Tuchman SA, Acharya C, Salter K, Gasparetto C, Zhan F et al. Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma. J Clin Oncol 2009; 27: 4197–4203.

    Article  CAS  Google Scholar 

  4. Chiecchio L, Dagrada GP, Protheroe RK, Stockley DM, Smith AG, Orchard KH et al. Loss of 1p and rearrangement of MYC are associated with progression of smouldering myeloma to myeloma: sequential analysis of a single case. Haematologica 2009; 94: 1024–1028.

    Article  CAS  Google Scholar 

  5. Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 2008; 13: 167–180.

    Article  CAS  Google Scholar 

  6. Chng WJ, Huang GF, Chung TH, Ng SB, Gonzalez-Paz N, Troska-Price T et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia 2011; 25: 1026–1035.

    Article  CAS  Google Scholar 

  7. Potter M . Neoplastic development in plasma cells. Immunol Rev 2003; 194: 177–195.

    Article  CAS  Google Scholar 

  8. Shou Y, Martelli ML, Gabrea A, Qi Y, Brents LA, Roschke A et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc Natl Acad Sci USA 2000; 97: 228–233.

    Article  CAS  Google Scholar 

  9. 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 

  10. Avet-Loiseau H, Gerson F, Magrangeas F, Minvielle S, Harousseau JL, Bataille R . Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 2001; 98: 3082–3086.

    Article  CAS  Google Scholar 

  11. Gabrea A, Martelli ML, Qi Y, Roschke A, Barlogie B, Shaughnessy Jr JD et al. Secondary genomic rearrangements involving immunoglobulin or MYC loci show similar prevalences in hyperdiploid and nonhyperdiploid myeloma tumors. Genes Chromosomes Cancer 2008; 47: 573–590.

    Article  CAS  Google Scholar 

  12. Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002; 99: 1745–1757.

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Hjertner O, Hjorth-Hansen H, Borset M, Seidel C, Waage A, Sundan A . Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells. Blood 2001; 97: 516–522.

    Article  CAS  Google Scholar 

  15. Kawamura C, Kizaki M, Yamato K, Uchida H, Fukuchi Y, Hattori Y et al. Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood 2000; 96: 2005–2011.

    CAS  PubMed  Google Scholar 

  16. Ro TB, Holt RU, Brenne AT, Hjorth-Hansen H, Waage A, Hjertner O et al. Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells. Oncogene 2004; 23: 3024–3032.

    Article  Google Scholar 

  17. Kersten C, Dosen G, Myklebust JH, Sivertsen EA, Hystad ME, Smeland EB et al. BMP-6 inhibits human bone marrow B lymphopoiesis--upregulation of Id1 and Id3. Exp Hematol 2006; 34: 72–81.

    Article  CAS  Google Scholar 

  18. Seckinger A, Meissner T, Moreaux J, Goldschmidt H, Fuhler GM, Benner A et al. Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis. Oncogene 2009; 28: 3866–3879.

    Article  CAS  Google Scholar 

  19. Grcevic D, Kusec R, Kovacic N, Lukic A, Lukic IK, Ivcevic S et al. Bone morphogenetic proteins and receptors are over-expressed in bone-marrow cells of multiple myeloma patients and support myeloma cells by inducing ID genes. Leuk Res 2010; 34: 742–751.

    Article  CAS  Google Scholar 

  20. Miyazono K, Kamiya Y, Morikawa M . Bone morphogenetic protein receptors and signal transduction. J Biochem 2010; 147: 35–51.

    Article  CAS  Google Scholar 

  21. Ren R, Charles PC, Zhang C, Wu Y, Wang H, Patterson C . Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses. Blood 2007; 109: 2847–2853.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Nohe A, Keating E, Knaus P, Petersen NO . Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004; 16: 291–299.

    Article  CAS  Google Scholar 

  23. Du J, Yang S, Wang Z, Zhai C, Yuan W, Lei R et al. Bone morphogenetic protein 6 inhibit stress-induced breast cancer cells apoptosis via both Smad and p38 pathways. J Cell Biochem 2008; 103: 1584–1597.

    Article  CAS  Google Scholar 

  24. Chen CR, Kang Y, Massague J . Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor beta growth arrest program. Proc Natl Acad Sci USA 2001; 98: 992–999.

    Article  CAS  Google Scholar 

  25. Frederick JP, Liberati NT, Waddell DS, Shi Y, Wang XF . Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element. Mol Cell Biol 2004; 24: 2546–2559.

    Article  CAS  Google Scholar 

  26. Yagi K, Furuhashi M, Aoki H, Goto D, Kuwano H, Sugamura K et al. c-myc is a downstream target of the Smad pathway. J Biol Chem 2002; 277: 854–861.

    Article  CAS  Google Scholar 

  27. Burger R, Guenther A, Bakker F, Schmalzing M, Bernand S, Baum W et al. Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma. Hematol J 2001; 2: 42–53.

    Article  CAS  Google Scholar 

  28. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol 2008; 4: 33–41.

    Article  CAS  Google Scholar 

  29. Fagerli UM, Holt RU, Holien T, Vaatsveen TK, Zhan F, Egeberg KW et al. Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood 2008; 111: 806–815.

    Article  CAS  Google Scholar 

  30. Ricci MS, Jin Z, Dews M, Yu D, Thomas-Tikhonenko A, Dicker DT et al. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol Cell Biol 2004; 24: 8541–8555.

    Article  CAS  Google Scholar 

  31. Cleveland JL, Huleihel M, Bressler P, Siebenlist U, Akiyama L, Eisenman RN et al. Negative regulation of c-myc transcription involves myc family proteins. Oncogene Res 1988; 3: 357–375.

    CAS  PubMed  Google Scholar 

  32. Evan G, Littlewood T . A matter of life and cell death. Science 1998; 281: 1317–1322.

    Article  CAS  Google Scholar 

  33. Murphy DJ, Junttila MR, Pouyet L, Karnezis A, Shchors K, Bui DA et al. Distinct thresholds govern Myc′s biological output in vivo. Cancer Cell 2008; 14: 447–457.

    Article  CAS  Google Scholar 

  34. Yin X, Giap C, Lazo JS, Prochownik EV . Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene 2003; 22: 6151–6159.

    Article  CAS  Google Scholar 

  35. Larsson LG, Henriksson MA . The Yin and Yang functions of the Myc oncoprotein in cancer development and as targets for therapy. Exp Cell Res 2010; 316: 1429–1437.

    Article  CAS  Google Scholar 

  36. Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol 2008; 10: 1199–1207.

    Article  CAS  Google Scholar 

  37. Norgaard NN, Holien T, Jonsson S, Hella H, Espevik T, Sundan A et al. CpG-oligodeoxynucleotide inhibits Smad-dependent bone morphogenetic protein signaling: effects on myeloma cell apoptosis and in vitro osteoblastogenesis. J Immunol 2010; 185: 3131–3139.

    Article  CAS  Google Scholar 

  38. Borset M, Hjorth-Hansen H, Johnsen AC, Seidel C, Waage A, Espevik T et al. Apoptosis, proliferation and NF-kappaB activation induced by agonistic Fas antibodies in the human myeloma cell line OH-2: amplification of Fas-mediated apoptosis by tumor necrosis factor. Eur J Haematol 1999; 63: 345–353.

    Article  CAS  Google Scholar 

  39. Erikson J, Finan J, Nowell PC, Croce CM . Translocation of immunoglobulin VH genes in Burkitt lymphoma. Proc Natl Acad Sci USA 1982; 79: 5611–5615.

    Article  CAS  Google Scholar 

  40. Lee CW, Ito K, Ito Y . Role of RUNX3 in bone morphogenetic protein signaling in colorectal cancer. Cancer Res 2010; 70: 4243–4252.

    Article  CAS  Google Scholar 

  41. Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 2003; 111: 1771–1782.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Berit Fladvad Størdal for excellent technical assistance. We wish to thank the staff at the Department of Hematology, St Olav's University Hospital, Trondheim, Norway and the Norwegian Myeloma Biobank for help obtaining primary myeloma samples. We thank Karin Fahl Wader for valuable help organizing clinical data from patients. We also acknowledge the support provided by the Norwegian Microarray Consortium (NMC), Trondheim, Norway. This work was funded by the Norwegian Cancer Society and the Norwegian Research Council.

Author information

Authors and Affiliations

  1. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    T Holien, T K Våtsveen, H Hella, C Rampa, G Brede, L A G Grøseth, M Rekvig, M Børset, T Standal, A Waage & A Sundan

  2. Department of Hematology, St Olav's University Hospital, Trondheim, Norway

    L A G Grøseth & A Waage

Authors
  1. T Holien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T K Våtsveen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Hella
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Rampa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Brede
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L A G Grøseth
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Rekvig
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Børset
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Standal
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Waage
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Sundan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Holien.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holien, T., Våtsveen, T., Hella, H. et al. Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC. Leukemia 26, 1073–1080 (2012). https://doi.org/10.1038/leu.2011.263

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.263

Keywords

This article is cited by

Search

Advanced search

Quick links