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The mechanistic role of epigenetic in multiple myeloma

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Abstract

Multiple myeloma (MM) is a B cell malignancy characterized by accumulation of malignant plasma cells in the bone marrow. Pathogenesis of MM involves a complex pattern of structural and numerical chromosomal aberrations. In addition, epigenetic changes such as DNA methylation and histone modifications may play a role in this disease by affecting the expression of different genes. This article reviews recent findings on the role of epigenetic alterations in MM pathogenesis, which affect the expression of cell cycle regulatory molecules, apoptosis, DNA repair system, CD markers, cell signaling pathways as well as tumor suppressor miRNAs. Given these results, it can be stated that these epigenetic changes play an important role in the initiation and progression of MM. Therefore, understanding the impact of epigenetics in MM pathogenesis in each stage of disease progression can help develop therapeutic targets to increase survival and reduce drug resistance.

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References

  • Abroun S, Saki N, Fakher R, Asghari F (2012) Biology and bioinformatics of myeloma cell. Lab Hematol Off Publ Int Soc Lab Hematol 18(4):30–41

    Google Scholar 

  • Barrena S, Almeida J, Yunta M, Lopez A, Fernandez-Mosteirin N, Giralt M et al (2005) Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia 19(8):1376–1383

    Article  CAS  PubMed  Google Scholar 

  • Benetatos L, Dasoula A, Hatzimichael E, Georgiou I, Syrrou M, Bourantas KL (2008) Promoter hypermethylation of the MEG3 (DLK1/MEG3) imprinted gene in multiple myeloma. Clin Lymphoma Myeloma 8(3):171–175

    Article  CAS  PubMed  Google Scholar 

  • Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J (2008) Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J Cell Sci 121(6):737–746

    Article  CAS  PubMed  Google Scholar 

  • Cea M, Cagnetta A, Gobbi M, Patrone F, Richardson PG, Hideshima T et al (2013) New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. Curr Pharm Des 19(4):734–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen G, Wang Y, Huang H, Lin F, Wu D, Sun A et al (2009) Combination of DNA methylation inhibitor 5‐azacytidine and arsenic trioxide has synergistic activity in myeloma. Eur J Haematol 82(3):176–183

    Article  CAS  PubMed  Google Scholar 

  • Chesi M, Bergsagel PL (2010) Epigenetics and microRNAs combine to modulate the MDM2/p53 axis in myeloma. Cancer Cell 18(4):299–300

    Article  CAS  PubMed  Google Scholar 

  • Chim C, Fung T, Liang R (2003) Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS. Leukemia 17(12):2533–2535

    Article  CAS  PubMed  Google Scholar 

  • Chim C-S, Fung T-K, Cheung W-C, Liang R, Kwong Y-L (2004) SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 103(12):4630–4635

    Article  CAS  PubMed  Google Scholar 

  • Chim C, Liang R, Fung T, Kwong Y (2005) Infrequent epigenetic dysregulation of CIP/KIP family of cyclin-dependent kinase inhibitors in multiple myeloma. Leukemia 19(12):2352–2355

    Article  CAS  PubMed  Google Scholar 

  • Chim C-S, Liang R, Fung T-K, Choi C-L, Kwong Y-L (2007a) Epigenetic dysregulation of the death-associated protein kinase/p14/HDM2/p53/Apaf-1 apoptosis pathway in multiple myeloma. J Clin Pathol 60(6):664–669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chim C, Pang R, Fung T, Choi C, Liang R (2007b) Epigenetic dysregulation of Wnt signaling pathway in multiple myeloma. Leukemia 21(12):2527–2536

    Article  CAS  PubMed  Google Scholar 

  • Chim CS, Kwong YL, Liang R (2008) Gene hypermethylation in multiple myeloma: lessons from a cancer pathway approach. Clin Lymphoma Myeloma 8(6):331–339

    Article  CAS  PubMed  Google Scholar 

  • de Boer J, Hoeijmakers JH (2000) Nucleotide excision repair and human syndromes. Carcinogenesis 21(3):453–460

    Article  PubMed  Google Scholar 

  • De Bruyne E, Bos TJ, Asosingh K, Broek IV, Menu E, Van Valckenborgh E et al (2008) Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival. Clin Cancer Res 14(10):2918–2926

    Article  PubMed  Google Scholar 

  • De Bruyne E, Bos TJ, Schuit F, Van Valckenborgh E, Menu E, Thorrez L et al (2010) IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood 115(12):2430–2440

    Article  PubMed  Google Scholar 

  • de Carvalho F, Colleoni GW, Almeida MS, Carvalho AL, Vettore AL (2009) TGFbetaR2 aberrant methylation is a potential prognostic marker and therapeutic target in multiple myeloma. Int J Cancer 125(8):1985–1991

    Article  PubMed  Google Scholar 

  • Drucker L, Tohami T, Tartakover-Matalon S, Zismanov V, Shapiro H, Radnay J et al (2006) Promoter hypermethylation of tetraspanin members contributes to their silencing in myeloma cell lines. Carcinogenesis 27(2):197–204

    Article  CAS  PubMed  Google Scholar 

  • Foltankova V, Legartová S, Kozubek S, Bartova E (2011) Tumor-specific histone signature and DNA methylation in multiple myeloma and leukemia cells. Neoplasma 59(4):450–462

    Article  Google Scholar 

  • Ghoshal P, Nganga AJ, Moran-Giuati J, Szafranek A, Johnson TR, Bigelow AJ et al (2009) Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. Cancer Res 69(10):4380–4387

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Paz N, Chng WJ, McClure RF, Blood E, Oken MM, Van Ness B et al (2007) Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications. Blood 109(3):1228–1232

    Article  CAS  PubMed  Google Scholar 

  • Heller G, Schmidt WM, Ziegler B, Holzer S, Müllauer L, Bilban M et al (2008) Genome-wide transcriptional response to 5-aza-2′-deoxycytidine and trichostatin a in multiple myeloma cells. Cancer Res 68(1):44–54

    Article  CAS  PubMed  Google Scholar 

  • Hideshima T, Anderson KC (2013) Histone deacetylase inhibitors in the treatment for multiple myeloma. Int J Hematol 97(3):324–332

    Article  CAS  PubMed  Google Scholar 

  • Hodge DR, Peng B, Cherry JC, Hurt EM, Fox SD, Kelley JA et al (2005a) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65(11):4673–4682

    Article  CAS  PubMed  Google Scholar 

  • Hodge DR, Peng B, Pompeia C, Thomas S, Cho E, Clausen PA et al (2005b) Research paper epigenetic silencing of manganese superoxide dismutase (SOD-2) in KAS 6/1 human multiple myeloma cells increases cell proliferation. Cancer Biol Ther 4(5):585–592

    Article  CAS  PubMed  Google Scholar 

  • Houde C, Li Y, Song L, Barton K, Zhang Q, Godwin J et al (2004) Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood 104(12):3697–3704

    Article  CAS  PubMed  Google Scholar 

  • Hurt EM, Thomas SB, Peng B, Farrar WL (2006) Research paper reversal of p53 epigenetic silencing in multiple myeloma permits apoptosis by a p53 activator. Cancer Biol Ther 5(9):1154–1160

    Article  CAS  PubMed  Google Scholar 

  • Hurt EM, Thomas SB, Peng B, Farrar WL (2007) Integrated molecular profiling of SOD2 expression in multiple myeloma. Blood 109(9):3953–3962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jost E, Gezer D, Wilop S, Suzuki H, Herman J, Osieka R et al (2009) Epigenetic dysregulation of secreted Frizzled-related proteins in multiple myeloma. Cancer Lett 281(1):24–31

    Article  CAS  PubMed  Google Scholar 

  • Jung S, Kim S, Gale M, Cherni I, Fonseca R, Carpten J et al (2012) DNA methylation in multiple myeloma is weakly associated with gene transcription. PLoS One 7(12):e52626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kocemba KA, Groen RW, Van Andel H, Kersten MJ, Mahtouk K, Spaargaren M et al (2012) Transcriptional silencing of the Wnt-antagonist DKK1 by promoter methylation is associated with enhanced Wnt signaling in advanced multiple myeloma. PLoS One 7(2):e30359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krieger S, Grunau C, Sabbah M, Sola B (2005) Cyclin D1 gene activation in human myeloma cells is independent of DNA hypomethylation or histone hyperacetylation. Exp Hematol 33(6):652–659

    Article  CAS  PubMed  Google Scholar 

  • Lavelle D, DeSimone J, Hankewych M, Kousnetzova T, Chen Y-H (2003) Decitabine induces cell cycle arrest at the G1 phase via p21WAF1 and the G2/M phase via the p38 MAP kinase pathway. Leuk Res 27(11):999–1007

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Yang Z-s, Song J-j, Liu Q, Chen J-b (2012) Protocadherin-10 is involved in angiogenesis and methylation correlated with multiple myeloma. Int J Mol Med 29(4):704

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Wang J, Epner EM (2004) Cyclin D1 activation in B-cell malignancy: association with changes in histone acetylation, DNA methylation, and RNA polymerase II binding to both promoter and distal sequences. Blood 104(8):2505–2513

    Article  CAS  PubMed  Google Scholar 

  • Luo S-Q, Hu J-P, Qu Q, Li J, Ren W, Zhang J-M et al (2012) The effects of promoter methylation on downregulation of DAZAP2 in multiple myeloma cell lines. PLoS One 7(7):e40475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maes K, Menu E, Van Valckenborgh E, Van Riet I, Vanderkerken K, De Bruyne E (2013) Epigenetic modulating agents as a new therapeutic approach in multiple myeloma. Cancers 5(2):430–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misiewicz-Krzeminska I, Sarasquete ME, Quwaider D, Krzeminski P, Ticona FV, Paíno T, et al (2012) Restoration of miR-214 expression reduces growth of myeloma cells through a positive regulation of P53 and inhibition of DNA replication. Haematologica. haematol.2012.070011

  • Peng B, Hodge DR, Thomas SB, Cherry JM, Munroe DJ, Pompeia C et al (2005) Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6-responsive multiple myeloma KAS-6/1 cells. J Biol Chem 280(6):4182–4187

    Article  CAS  PubMed  Google Scholar 

  • Peng B, Hurt EM, Hodge DR, Thomas SB, Farrar WL (2006) Research paper DNA hypermethylation and partial gene silencing of human thymine-DNA glycosylase in multiple myeloma cell lines. Epigenetics 1(3):138–145

    Article  PubMed  Google Scholar 

  • Peng L, Yang Z, Tan C, Ren G, Chen J (2013) Epigenetic inactivation of ADAMTS9 via promoter methylation in multiple myeloma. Mol Med Rep 7(3):1055–1061

    CAS  PubMed  Google Scholar 

  • Polakova KM, Koblihova J, Stopka T (2013) Role of epigenetics in chronic myeloid leukemia. Curr Hematol Malig Rep 8(1):28–36

    Article  Google Scholar 

  • Pompeia C, Hodge DR, Plass C, Wu Y-Z, Marquez VE, Kelley JA et al (2004) Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line. Cancer Res 64(10):3465–3473

    Article  CAS  PubMed  Google Scholar 

  • Pratt G (2013) Histone deacetylase inhibitors in multiple myeloma. Lancet Oncol 14(11):1038–1039

    Article  CAS  PubMed  Google Scholar 

  • Ribas C, Colleoni GW, Felix RS, Regis Silva MR, Caballero OL, Brait M et al (2005) p16 gene methylation lacks correlation with angiogenesis and prognosis in multiple myeloma. Cancer Lett 222(2):247–254

    Article  CAS  PubMed  Google Scholar 

  • Saki N, Abroun S, Hajizamani S, Rahim F, Shahjahani M (2013) Association of chromosomal translocation and miRNA expression with the pathogenesis of multiple myeloma. Cell J 16(2)

  • Scholz B, Marschalek R (2012) Epigenetics and blood disorders. Br J Haematol 158(3):307–322

    Article  CAS  PubMed  Google Scholar 

  • Seidl S, Kaufmann H, Drach J (2003) New insights into the pathophysiology of multiple myeloma. Lancet Oncol 4(9):557–564

    Article  CAS  PubMed  Google Scholar 

  • Slupphaug G, Kavli B, Krokan HE (2003) The interacting pathways for prevention and repair of oxidative DNA damage. Mutat Res Fundam Mol Mech Mutagen 531(1):231–251

    Article  CAS  Google Scholar 

  • Smith EM, Boyd K, Davies FE (2010) The potential role of epigenetic therapy in multiple myeloma. Br J Haematol 148(5):702–713

    Article  CAS  PubMed  Google Scholar 

  • Stühmer T, Chatterjee M, Hildebrandt M, Herrmann P, Gollasch H, Gerecke C et al (2005) Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 106(10):3609–3617

    Article  PubMed  Google Scholar 

  • Ullmannova-Benson V, Guan M, Zhou X, Tripathi V, Yang X-Y, Zimonjic DB et al (2008) DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway. Leukemia 23(2):383–390

    Article  PubMed  PubMed Central  Google Scholar 

  • Wilop S, van Gemmeren TB, Lentjes M, van Engeland M, Herman JG, Brummendorf T et al (2011) Methylation-associated dysregulation of the suppressor of cytokine signaling-3 gene in multiple myeloma. Epigenetics 6(8):1047–1052

    Article  CAS  PubMed  Google Scholar 

  • Wong KY, Yim RLH, So CC, Jin D-Y, Liang R, Chim CS (2011a) Epigenetic inactivation of the MIR34B/C in multiple myeloma. Blood 118(22):5901–5904

    Article  CAS  PubMed  Google Scholar 

  • Wong KY, Liang R, So CC, Jin DY, Costello JF, Chim CS (2011b) Epigenetic silencing of MIR203 in multiple myeloma. Br J Haematol 154(5):569–578

    Article  CAS  PubMed  Google Scholar 

  • Wong KY, So CC, Loong F, Chung LP, Lam WWL, Liang R et al (2011c) Epigenetic inactivation of the miR-124-1 in haematological malignancies. PLoS One 6(4):e19027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong KY, Huang X, Chim CS (2012) DNA methylation of microRNA genes in multiple myeloma. Carcinogenesis. bgs212

  • Wong K-Y, Yim RL-H, Kwong Y-L, Leung C-Y, Hui P-K, Cheung F et al (2013) Epigenetic inactivation of the MIR129-2 in hematological malignancies. J Hematol Oncol 6:16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuregir OO, Yurtcu E, Kizilkilic E, Kocer N, Ozdogu H, Sahin F (2010) Detecting methylation patterns of p16, MGMT, DAPK and E‐cadherin genes in multiple myeloma patients. Int J Lab Hematol 32(2):142–149

    Article  PubMed  Google Scholar 

  • Zhang W, Wang YE, Zhang Y, Leleu X, Reagan M, Zhang Y et al (2014) Global epigenetic regulation of microRNAs in multiple myeloma. PLoS One 9(10):e110973

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao F, Chen Y, Li R, Liu Y, Wen L, Zhang C (2010a) Triptolide alters histone H3K9 and H3K27 methylation state and induces G0/G1 arrest and caspase-dependent apoptosis in multiple myeloma in vitro. Toxicology 267(1):70–79

    Article  CAS  PubMed  Google Scholar 

  • Zhao F, Chen Y, Zeng L, Li R, Zeng R, Wen L et al (2010b) Role of triptolide in cell proliferation, cell cycle arrest, apoptosis and histone methylation in multiple myeloma U266 cells. Eur J Pharmacol 646(1):1–11

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank all of our colleagues in Shafa Hospital and Allied Health Sciences School, Ahvaz

Jundishapur University of Medical Sciences.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Saeideh Hajizamani, Neda Golchin, Mohammad Shahjahani, Tina Vosoughi, Homayon Yousefi & Najmaldin Saki

  2. Research Center of Cancer, Shiraz University of Medical Sciences, Shiraz, Iran

    Gholam Hossein Tamaddon

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  1. Saeideh Hajizamani
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  2. Neda Golchin
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  3. Mohammad Shahjahani
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  4. Gholam Hossein Tamaddon
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  5. Tina Vosoughi
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  6. Homayon Yousefi
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  7. Najmaldin Saki
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Correspondence to Najmaldin Saki.

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Hajizamani, S., Golchin, N., Shahjahani, M. et al. The mechanistic role of epigenetic in multiple myeloma. Comp Clin Pathol 25, 1279–1288 (2016). https://doi.org/10.1007/s00580-015-2074-3

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