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Profiling Bortezomib Resistance in Multiple Myeloma: Implications in Personalized Pharmacotherapy

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

Abstract

Treatment regimens for MM patients have undergone considerable modifications from the 1960s in an attempt to achieve that elusive “complete cure.” Proteasome inhibitors such as bortezomib (Bz) have recently become effective chemotherapeutic agents in the treatment of MM, used alone or in combination with other anticancer agents like alkylating agents, immunomodulators (IMiDs), topoisomerase inhibitors, corticosteroids, and histone deacetylase inhibitors (HDACis). However, wide interindividual variation in response to treatment with Bz is a major limitation in achieving consistent therapeutic effect in MM. In addition, patients who respond commonly develop resistance to proteasome inhibitors, with subsequent aggressive relapses. Drug resistance may be categorized into innate resistance with nonspecific resistance already present in Bz-refractory drug-naive patients who never respond to Bz treatment or emerging (acquired) resistance where a patient’s tumor cells “acquire” the ability to resist therapy in the course of treatment leading to eventual Bz-resistant relapse. We discuss molecular profiling approaches to characterize bortezomib resistance, including analysis of genomic variations, gene expression patterns, epigenetic patterns, and protein patterns. We conclude that robust approaches using multiple data types are of primary importance in profiling drug resistance in MM. The ultimate purpose of such an effort will be to create a pharmacogenomic profiling-guided therapeutic response score that can be cross-validated using clinical trials on MM patients undergoing Bz-based therapy or any chemotherapy, so that it can be routinely applied in clinical settings to improve selective response to available drugs, predict effective combinations, and identify secondary therapies to circumvent the challenges in the relapsed patient.

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Abbreviations

alloSCT:

Allogeneic stem cell transplantation

autoSCT:

Autologous stem cell transplantation

BMSCs:

Bone marrow stromal cells

Bz:

Bortezomib/Velcade®

ChIP:

Chromatin immunoprecipitation

CMAP:

Connectivity map

COBRA:

Combined bisulfite restriction analysis

CR:

Complete response

CRD:

Complete response duration

Cz:

Carfilzomib/Kyprolis®

Dex:

Dexamethasone

EMD:

Extramedullary disease

ERK:

Extracellular signal-regulated kinase

FDA:

Food and Drug Administration

FGF:

Fibroblast growth factor

GEP:

Gene expression profiling

GSEA:

Gene set enrichment analysis

HDACis:

Histone deacetylase inhibitors

HPLC:

High-performance liquid chromatography

IGF-1:

Insulin-like growth factor 1

IL-6:

Interleukin 6

IM:

Intermediate metabolizers

IMiDs:

Immunomodulatory drugs

JAK:

Janus kinase

KMT:

Lysine methyltransferases

LPS:

Lipopolysaccharide

5-mC:

5-Methylcytosine

MDR1:

Multidrug resistance 1 or P-glycoprotein

MEK:

RAS/RAF/MAPK kinase

MGUS:

Monoclonal gammopathy of undetermined significance

MM:

Multiple myeloma

MM-BMSCs:

MM cells and bone marrow stromal cells

MR:

Minimal response

MSDA:

Multiple linear discriminant analysis

Ms-SNuPE:

Methylation-sensitive single-nucleotide primer extension

NC:

No change

NGS:

Next-generation sequencing

OS:

Overall survival

PD:

Progressive disease

PI3K:

Phosphatidylinositol-3 kinase

PLD:

Pegylated liposomal doxorubicin

PM:

Poor metabolizers

PN:

Peripheral neuropathy

PR:

Partial response

PSGL-1:

P-selectin glycoprotein ligand-1

SDF-1α:

SC-derived factor 1α

SMM:

Smoldering multiple myeloma

SNPs:

Single-nucleotide polymorphisms (or “snips”)

STAT3:

Signal transducers and activators of transcription 3

TNF:

Tumor necrosis factor

TNT:

Time-to-next treatment

TT3:

Total therapy 3

UPR:

Unfolded protein response

VEGF:

Vascular endothelial growth factor

VRC2:

Velcade resensitizing compound 2

References

  1. Kuehl WM, Bergsagel PL (2012) Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest 122(10):3456–3463

    PubMed  CAS  PubMed Central  Google Scholar 

  2. Herve AL, Florence M, Philippe M et al (2011) Molecular heterogeneity of multiple myeloma: pathogenesis, prognosis, and therapeutic implications. J Clin Oncol 29(14): 1893–1897

    PubMed  Google Scholar 

  3. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (2009) Multiple myeloma. Lancet 374(9686):324–339

    PubMed  Google Scholar 

  4. Rajkumar SV (2013) Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol 88(3):226–235

    PubMed  Google Scholar 

  5. Mahindra A, Hideshima T, Anderson KC (2010) Multiple myeloma: biology of the disease. Blood Rev 24(Suppl 1):S5–S11

    PubMed  Google Scholar 

  6. Landgren O, Kyle RA, Pfeiffer RM et al (2009) Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113(22):5412–5417

    PubMed  CAS  PubMed Central  Google Scholar 

  7. International Myeloma Working Group (2003) Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121(5):749–757

    Google Scholar 

  8. Kyle RA, Rajkumar SV (2007) Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. Br J Haematol 139(5):730–743

    PubMed  CAS  Google Scholar 

  9. Kyle RA, Therneau TM, Rajkumar SV et al (2002) A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 346(8):564–569

    PubMed  Google Scholar 

  10. Blade J, Rosinol L, Cibeira MT, de Larrea CF (2008) Pathogenesis and progression of monoclonal gammopathy of undetermined significance. Leukemia 22(9):1651–1657

    PubMed  CAS  Google Scholar 

  11. Munshi NC, Anderson KC (2013) New strategies in the treatment of multiple myeloma. Clin Cancer Res 19(13):3337–3344

    PubMed  CAS  PubMed Central  Google Scholar 

  12. Hoogstraten B, Sheehe PR, Cuttner J et al (1967) Melphalan in multiple myeloma. Blood 30(1):74–83

    PubMed  CAS  Google Scholar 

  13. Oken MM, Harrington DP, Abramson N, Kyle RA, Knospe W, Glick JH (1997) Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 79(8):1561–1567

    PubMed  CAS  Google Scholar 

  14. Alexanian R, Haut A, Khan AU et al (1969) Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA 208(9):1680–1685

    PubMed  CAS  Google Scholar 

  15. Anonymous (1998) Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists’ Collaborative Group. J Clin Oncol 16(12):3832–3842

    Google Scholar 

  16. Koreth J, Cutler CS, Djulbegovic B et al (2007) High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 13(2):183–196

    PubMed  CAS  Google Scholar 

  17. Bensinger WI (2002) Allogeneic hematopoietic cell transplantation for multiple myeloma. Biomed Pharmacother 56(3):133–138

    PubMed  CAS  Google Scholar 

  18. Maloney DG, Molina AJ, Sahebi F et al (2003) Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102(9):3447–3454

    PubMed  CAS  Google Scholar 

  19. Samson D, Gaminara E, Newland A et al (1989) Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet 2(8668):882–885

    PubMed  CAS  Google Scholar 

  20. Dimopoulos MA, San-Miguel JF, Anderson KC (2011) Emerging therapies for the treatment of relapsed or refractory multiple myeloma. Eur J Haematol 86(1):1–15

    PubMed  CAS  Google Scholar 

  21. Mitsiades CS, Davies FE, Laubach JP et al (2011) Future directions of next-generation novel therapies, combination approaches, and the development of personalized medicine in myeloma. J Clin Oncol 29(14):1916–1923

    PubMed  Google Scholar 

  22. Moreau P, Richardson PG, Cavo M et al (2012) Proteasome inhibitors in multiple myeloma: 10 years later. Blood 120(5):947–959

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Kortuem KM, Stewart AK (2013) Carfilzomib. Blood 121(6):893–897

    PubMed  CAS  Google Scholar 

  24. Potts BC, Albitar MX, Anderson KC et al (2011) Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets 11(3):254–284

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Hideshima T, Richardson P, Chauhan D et al (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61(7):3071–3076

    PubMed  CAS  Google Scholar 

  26. Hideshima T, Mitsiades C, Akiyama M et al (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101(4):1530–1534

    PubMed  CAS  Google Scholar 

  27. Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–2622

    PubMed  CAS  Google Scholar 

  28. Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46(5):673–683

    PubMed  CAS  Google Scholar 

  29. LeBlanc R, Catley LP, Hideshima T et al (2002) Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 62(17): 4996–5000

    PubMed  CAS  Google Scholar 

  30. Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498

    PubMed  CAS  Google Scholar 

  31. Dispenzieri A, Kyle RA (2005) Neurological aspects of multiple myeloma and related disorders. Best Pract Res Clin Haematol 18(4):673–688

    PubMed  CAS  Google Scholar 

  32. Richardson PG, Briemberg H, Jagannath S et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24(19):3113–3120

    PubMed  CAS  Google Scholar 

  33. Barlogie B, van Rhee F, Shaughnessy JD Jr et al (2008) Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood 112(8):3122–3125

    PubMed  CAS  PubMed Central  Google Scholar 

  34. San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917

    PubMed  CAS  Google Scholar 

  35. Fonseca R, Bergsagel PL, Drach J et al (2009) International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 23(12):2210–2221

    PubMed  CAS  PubMed Central  Google Scholar 

  36. Vangsted A, Klausen TW, Vogel U (2012) Genetic variations in multiple myeloma II: association with effect of treatment. Eur J Haematol 88(2):93–117

    PubMed  CAS  Google Scholar 

  37. Richardson PG, Sonneveld P, Schuster MW et al (2007) Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol 137(5):429–435

    PubMed  CAS  Google Scholar 

  38. Richardson PG, Sonneveld P, Schuster M et al (2007) Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 110(10): 3557–3560

    PubMed  CAS  Google Scholar 

  39. Laubach J, Richardson P, Anderson K (2011) Multiple myeloma. Annu Rev Med 62:249–264

    PubMed  CAS  Google Scholar 

  40. Kumar S, Rajkumar SV (2008) Many facets of bortezomib resistance/susceptibility. Blood 112(6):2177–2178

    PubMed  CAS  Google Scholar 

  41. Grigorieva I, Thomas X, Epstein J (1998) The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone. Exp Hematol 26(7):597–603

    PubMed  CAS  Google Scholar 

  42. Rowley M, Liu P, Van Ness B (2000) Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood 96(9):3175–3180

    PubMed  CAS  Google Scholar 

  43. Mitsiades CS, Mitsiades N, Poulaki V et al (2002) Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 21(37):5673–5683

    PubMed  CAS  Google Scholar 

  44. Chauhan D, Uchiyama H, Akbarali Y et al (1996) Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87(3):1104–1112

    PubMed  CAS  Google Scholar 

  45. Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC (2001) The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20(33):4519–4527

    PubMed  CAS  Google Scholar 

  46. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 7(8):585–598

    PubMed  CAS  Google Scholar 

  47. Caers J, Van Valckenborgh E, Menu E, Van Camp B, Vanderkerken K (2008) Unraveling the biology of multiple myeloma disease: cancer stem cells, acquired intracellular changes and interactions with the surrounding micro-environment. Bull Cancer 95(3):301–313

    PubMed  CAS  Google Scholar 

  48. Urashima M, Chauhan D, Uchiyama H, Freeman GJ, Anderson KC (1995) CD40 ligand triggered interleukin-6 secretion in multiple myeloma. Blood 85(7):1903–1912

    PubMed  CAS  Google Scholar 

  49. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC (2004) Advances in biology of multiple myeloma: clinical applications. Blood 104(3):607–618

    PubMed  CAS  Google Scholar 

  50. Zang MR, Li F, An G et al (2012) Regulation of miRNA-15a/-16 expression on the drug resistance of myeloma cells. Zhonghua Yi Xue Za Zhi 92(16):1100–1103

    PubMed  Google Scholar 

  51. Hao M, Zhang L, An G et al (2011) Bone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing microRNA-15a expression. Leuk Lymphoma 52(9):1787–1794

    PubMed  CAS  Google Scholar 

  52. Wang X, Li C, Ju S, Wang Y, Wang H, Zhong R (2011) Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation. Leuk Lymphoma 52(10):1991–1998

    PubMed  CAS  Google Scholar 

  53. Kalitin NN, Kostyukova MN, Kakpakova ES, Tupitsyn NN, Karamysheva AF (2012) Expression of vascular endothelial growth factor receptors VEGFR1 in cultured multiple myeloma cells: correlation with immunophenotype and drug resistance. Bull Exp Biol Med 153(6):882–885

    PubMed  CAS  Google Scholar 

  54. Kuhn DJ, Berkova Z, Jones RJ et al (2012) Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma. Blood 120(16):3260–3270

    PubMed  CAS  PubMed Central  Google Scholar 

  55. Tai YT, Li XF, Catley L et al (2005) Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 65(24):11712–11720

    PubMed  CAS  Google Scholar 

  56. Azab AK, Runnels JM, Pitsillides C et al (2009) CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 113(18):4341–4351

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4(5): 349–360

    PubMed  CAS  Google Scholar 

  58. Lichter DI, Danaee H, Pickard MD et al (2012) Sequence analysis of beta-subunit genes of the 20S proteasome in patients with relapsed multiple myeloma treated with bortezomib or dexamethasone. Blood 120(23):4513–4516

    PubMed  CAS  PubMed Central  Google Scholar 

  59. Verbrugge SE, Al M, Assaraf YG et al (2013) Overcoming bortezomib resistance in human B cells by anti-CD20/rituximab-mediated complement-dependent cytotoxicity and epoxyketone-based irreversible proteasome inhibitors. Exp Hematol Oncol 2(1):2. doi:10.1186/2162-3619-2-2

    PubMed  CAS  PubMed Central  Google Scholar 

  60. Verbrugge SE, Assaraf YG, Dijkmans BA et al (2012) Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis. J Pharmacol Exp Ther 341(1):174–182

    PubMed  CAS  Google Scholar 

  61. Suzuki E, Demo S, Deu E et al (2011) Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 6(12):e27996

    PubMed  CAS  PubMed Central  Google Scholar 

  62. de Wilt LH, Jansen G, Assaraf YG et al (2012) Proteasome-based mechanisms of intrinsic and acquired bortezomib resistance in non-small cell lung cancer. Biochem Pharmacol 83(2):207–217

    PubMed  Google Scholar 

  63. Li X, Wood TE, Sprangers R et al (2010) Effect of noncompetitive proteasome inhibition on bortezomib resistance. J Natl Cancer Inst 102(14):1069–1082

    PubMed  CAS  Google Scholar 

  64. Franke NE, Niewerth D, Assaraf YG et al (2012) Impaired bortezomib binding to mutant beta5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia 26(4):757–768

    PubMed  CAS  Google Scholar 

  65. Lu SQ, Yang JM, Huang CM et al (2011) Comparison of protein expression profiles between bortezomib-resistant JurkatB cells with PSMB5 mutation and their parent cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi 19(4):869–873

    PubMed  CAS  Google Scholar 

  66. Ri M, Iida S, Nakashima T et al (2010) Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia 24(8):1506–1512

    PubMed  CAS  Google Scholar 

  67. Lu S, Chen Z, Yang J et al (2008) Overexpression of the PSMB5 gene contributes to bortezomib resistance in T-lymphoblastic lymphoma/leukemia cells derived from Jurkat line. Exp Hematol 36(10):1278–1284

    PubMed  CAS  Google Scholar 

  68. Lu S, Yang J, Song X et al (2008) Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib-selected variants of Jurkat T cell lymphoblastic lymphoma/leukemia line. J Pharmacol Exp Ther 326(2):423–431

    PubMed  CAS  Google Scholar 

  69. Lu S, Yang J, Chen Z et al (2009) Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Exp Hematol 37(7):831–837

    PubMed  Google Scholar 

  70. Oerlemans R, Franke NE, Assaraf YG et al (2008) Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112(6):2489–2499

    PubMed  CAS  Google Scholar 

  71. Shuqing L, Jianmin Y, Chongmei H, Hui C, Wang J (2011) Upregulated expression of the PSMB5 gene may contribute to drug resistance in patient with multiple myeloma when treated with bortezomib-based regimen. Exp Hematol 39(12):1117–1118

    PubMed  Google Scholar 

  72. Politou M, Karadimitris A, Terpos E, Kotsianidis I, Apperley JF, Rahemtulla A (2006) No evidence of mutations of the PSMB5 (beta-5 subunit of proteasome) in a case of myeloma with clinical resistance to bortezomib. Leuk Res 30(2):240–241

    PubMed  CAS  Google Scholar 

  73. Wang L, Kumar S, Fridley BL et al (2008) Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics. Clin Cancer Res 14(11):3503–3513

    PubMed  CAS  PubMed Central  Google Scholar 

  74. Balsas P, Galan-Malo P, Marzo I, Naval J (2012) Bortezomib resistance in a myeloma cell line is associated to PSMbeta5 overexpression and polyploidy. Leuk Res 36(2):212–218

    PubMed  CAS  Google Scholar 

  75. Barbone D, Cheung P, Battula S et al (2012) Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression. PLoS One 7(12):e52753

    PubMed  CAS  PubMed Central  Google Scholar 

  76. Yeom SY, Lee SJ, Kim WS, Park C (2012) Rad knockdown induces mitochondrial apoptosis in bortezomib resistant leukemia and lymphoma cells. Leuk Res 36(9):1172–1178

    PubMed  CAS  Google Scholar 

  77. Zhang L, Littlejohn JE, Cui Y, Cao X, Peddaboina C, Smythe WR (2010) Characterization of bortezomib-adapted I-45 mesothelioma cells. Mol Cancer 9:110. doi:10.1186/1476-4598-9-110

    PubMed  PubMed Central  Google Scholar 

  78. Ling X, Calinski D, Chanan-Khan AA, Zhou M, Li F (2010) Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types. J Exp Clin Cancer Res 29:8. doi:10.1186/1756-9966-29-8

    PubMed  PubMed Central  Google Scholar 

  79. Hu J, Dang N, Menu E et al (2012) Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition. Blood 119(3):826–837

    PubMed  CAS  Google Scholar 

  80. Smith AJ, Dai H, Correia C et al (2011) Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. J Biol Chem 286(20):17682–17692

    PubMed  CAS  PubMed Central  Google Scholar 

  81. Liu P, Xu B, Li J, Lu H (2009) BAG3 gene silencing sensitizes leukemic cells to bortezomib-induced apoptosis. FEBS Lett 583(2):401–406

    PubMed  CAS  Google Scholar 

  82. Yang TM, Barbone D, Fennell DA, Broaddus VC (2009) Bcl-2 family proteins contribute to apoptotic resistance in lung cancer multicellular spheroids. Am J Respir Cell Mol Biol 41(1):14–23

    PubMed  CAS  PubMed Central  Google Scholar 

  83. Xu D, Hu J, De Bruyne E et al (2012) Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. Biochem Biophys Res Commun 428(4): 518–524

    PubMed  CAS  Google Scholar 

  84. Kim A, Park S, Lee JE et al (2012) The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells. Leuk Res 36(7):912–920

    PubMed  CAS  Google Scholar 

  85. Hegde GV, Nordgren TM, Munger CM et al (2012) Novel therapy for therapy-resistant mantle cell lymphoma: multipronged approach with targeting of hedgehog signaling. Int J Cancer 131(12):2951–2960

    PubMed  CAS  Google Scholar 

  86. Jung HJ, Chen Z, Wang M et al (2012) Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities. Blood 119(11):2568–2578

    PubMed  CAS  PubMed Central  Google Scholar 

  87. Markovina S, Callander NS, O’Connor SL et al (2008) Bortezomib-resistant nuclear factor-kappaB activity in multiple myeloma cells. Mol Cancer Res 6(8):1356–1364

    PubMed  CAS  PubMed Central  Google Scholar 

  88. Markovina S, Callander NS, O’Connor SL et al (2010) Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells. Mol Cancer 9:176. doi:10.1186/1476-4598-9-176

    PubMed  PubMed Central  Google Scholar 

  89. Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S (2008) Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer 7:40. doi:10.1186/1476-4598-7-40

    PubMed  PubMed Central  Google Scholar 

  90. Landowski TH, Olashaw NE, Agrawal D, Dalton WS (2003) Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells. Oncogene 22(16):2417–2421

    PubMed  CAS  Google Scholar 

  91. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS (2000) Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19(38):4319–4327

    PubMed  CAS  Google Scholar 

  92. Shi L, Wang S, Zangari M et al (2010) Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance. Oncotarget 1(1):22–33

    PubMed  PubMed Central  Google Scholar 

  93. Que W, Chen J, Chuang M, Jiang D (2012) Knockdown of c-Met enhances sensitivity to bortezomib in human multiple myeloma U266 cells via inhibiting Akt/mTOR activity. APMIS 120(3):195–203

    PubMed  CAS  Google Scholar 

  94. Moriuchi M, Ohmachi K, Kojima M et al (2010) Three cases of bortezomib-resistant multiple myeloma with extramedullary masses. Tokai J Exp Clin Med 35(1):17–20

    PubMed  CAS  Google Scholar 

  95. Pirrotta MT, Gozzetti A, Cerase A et al (2008) Unusual discordant responses in two multiple myeloma patients during bortezomib treatment. Onkologie 31(1–2):45–47

    PubMed  Google Scholar 

  96. Filipczak PT, Piglowski W, Glowala-Kosinska M, Krawczyk Z, Scieglinska D (2012) HSPA2 overexpression protects V79 fibroblasts against bortezomib-induced apoptosis. Biochem Cell Biol 90(2):224–231

    PubMed  CAS  Google Scholar 

  97. Mozos A, Roue G, Lopez-Guillermo A et al (2011) The expression of the endoplasmic reticulum stress sensor BiP/GRP78 predicts response to chemotherapy and determines the efficacy of proteasome inhibitors in diffuse large b-cell lymphoma. Am J Pathol 179(5):2601–2610

    PubMed  CAS  PubMed Central  Google Scholar 

  98. Rushworth SA, Bowles KM, MacEwan DJ (2011) High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors. Cancer Res 71(5): 1999–2009

    PubMed  CAS  Google Scholar 

  99. Kern J, Untergasser G, Zenzmaier C et al (2009) GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. Blood 114(18):3960–3967

    PubMed  CAS  Google Scholar 

  100. Du ZX, Zhang HY, Meng X, Guan Y, Wang HQ (2009) Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells. BMC Cancer 9:56. doi:10.1186/1471-2407-9-56

    PubMed  PubMed Central  Google Scholar 

  101. Chauhan D, Li G, Shringarpure R et al (2003) Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 63(19):6174–6177

    PubMed  CAS  Google Scholar 

  102. Shringarpure R, Catley L, Bhole D et al (2006) Gene expression analysis of B-lymphoma cells resistant and sensitive to bortezomib. Br J Haematol 134(2):145–156

    PubMed  CAS  Google Scholar 

  103. Zhao M, Vuori K (2011) The docking protein p130Cas regulates cell sensitivity to proteasome inhibition. BMC Biol 9:73. doi:10.1186/1741-7007-9-73

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Jia L, Gopinathan G, Sukumar JT, Gribben JG (2012) Blocking autophagy prevents bortezomib-induced NF-kappaB activation by reducing I-kappaB alpha degradation in lymphoma cells. PLoS One 7(2):e32584

    PubMed  CAS  PubMed Central  Google Scholar 

  105. Rzymski T, Milani M, Singleton DC, Harris AL (2009) Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell Cycle 8(23):3838–3847

    PubMed  CAS  Google Scholar 

  106. Milani M, Rzymski T, Mellor HR et al (2009) The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with bortezomib. Cancer Res 69(10):4415–4423

    PubMed  CAS  Google Scholar 

  107. Nawrocki ST, Carew JS, Pino MS et al (2006) Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 66(7):3773–3781

    PubMed  CAS  Google Scholar 

  108. Mulligan G, Mitsiades C, Bryant B et al (2007) Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 109(8): 3177–3188

    PubMed  CAS  Google Scholar 

  109. Shaughnessy JD Jr, Zhan F, Burington BE et al (2007) A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109(6):2276–2284

    PubMed  CAS  Google Scholar 

  110. Zhan F, Barlogie B, Mulligan G, Shaughnessy JD Jr, Bryant B (2008) High-risk myeloma: a gene expression based risk-stratification model for newly diagnosed multiple myeloma treated with high-dose therapy is predictive of outcome in relapsed disease treated with single-agent bortezomib or high-dose dexamethasone. Blood 111(2):968–969

    PubMed  CAS  PubMed Central  Google Scholar 

  111. Nair B, van Rhee F, Shaughnessy JD Jr et al (2010) Superior results of total therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood 115(21):4168–4173

    PubMed  CAS  PubMed Central  Google Scholar 

  112. Shaughnessy JD Jr, Qu P, Usmani S et al (2011) Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with total therapy 3. Blood 118(13):3512–3524

    PubMed  CAS  PubMed Central  Google Scholar 

  113. Stessman HA, Baughn LB, Sarver A et al (2013) Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther 12(6):1140–1150

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Fernandez de Larrea C, Martin-Antonio B, Cibeira MT et al (2013) Impact of global and gene-specific DNA methylation pattern in relapsed multiple myeloma patients treated with bortezomib. Leuk Res 37(6):641–646

    PubMed  CAS  Google Scholar 

  115. Buda G, Ricci D, Huang CC et al (2010) Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin. Ann Hematol 89(11):1133–1140

    PubMed  CAS  PubMed Central  Google Scholar 

  116. Du J, Huo J, Shi J et al (2011) Polymorphisms of nuclear factor-kappaB family genes are associated with development of multiple myeloma and treatment outcome in patients receiving bortezomib-based regimens. Haematologica 96(5):729–737

    PubMed  CAS  PubMed Central  Google Scholar 

  117. Vangsted AJ, Soeby K, Klausen TW et al (2010) No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with multiple myeloma. BMC Cancer 10:404. doi:10.1186/1471-2407-10-404

    PubMed  PubMed Central  Google Scholar 

  118. Vangsted AJ, Klausen TW, Abildgaard N et al (2011) Single nucleotide polymorphisms in the promoter region of the IL1B gene influence outcome in multiple myeloma patients treated with high-dose chemotherapy independently of relapse treatment with thalidomide and bortezomib. Ann Hematol 90(10):1173–1181

    PubMed  CAS  Google Scholar 

  119. Broyl A, Corthals SL, Jongen JL et al (2010) Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol 11(11): 1057–1065

    PubMed  CAS  Google Scholar 

  120. Favis R, Sun Y, van de Velde H et al (2011) Genetic variation associated with bortezomib-induced peripheral neuropathy. Pharmacogenet Genomics 21(3):121–129

    PubMed  CAS  Google Scholar 

  121. Zhu YX, Tiedemann R, Shi CX et al (2011) RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5. Blood 117(14): 3847–3857

    PubMed  CAS  PubMed Central  Google Scholar 

  122. Stessman HA, Mansoor A, Zhan F, Linden MA, Van Ness B, Baughn LB (2013) Bortezomib resistance can be reversed by induced expression of plasma cell maturation markers in a mouse in vitro model of multiple myeloma. PLoS One 8(10):e77608

    Google Scholar 

  123. Leung-Hagesteijn C, Erdmann N, Cheung G et al (2013) Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 24(3):289–304

    PubMed  CAS  PubMed Central  Google Scholar 

  124. Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617

    PubMed  CAS  Google Scholar 

  125. Jagannath S, Barlogie B, Berenson J et al (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127(2):165–172

    PubMed  CAS  Google Scholar 

  126. Blade J, Samson D, Reece D et al (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 102(5):1115–1123

    PubMed  CAS  Google Scholar 

  127. Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550

    PubMed  CAS  PubMed Central  Google Scholar 

  128. Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36(3):842–854

    Google Scholar 

  129. van Rhee F, Bolejack V, Hollmig K et al (2007) High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis. Blood 110(3):827–832

    PubMed  PubMed Central  Google Scholar 

  130. Barlogie B, Anaissie E, van Rhee F et al (2007) Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br J Haematol 138(2):176–185

    PubMed  CAS  Google Scholar 

  131. Pineda-Roman M, Zangari M, Haessler J et al (2008) Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol 140(6):625–634

    PubMed  CAS  PubMed Central  Google Scholar 

  132. Lamb J (2007) The connectivity map: a new tool for biomedical research. Nat Rev Cancer 7(1):54–60

    PubMed  CAS  Google Scholar 

  133. Lamb J, Crawford ED, Peck D et al (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313(5795):1929–1935

    PubMed  CAS  Google Scholar 

  134. Van Ness B, Stessman H, Baughn LB, et al (2013) Strategies to identify effective treatments for proteasome inhibitor resistant multiple myeloma [abstract]. ASH Abstract

    Google Scholar 

  135. Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1):12–27

    PubMed  CAS  Google Scholar 

  136. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes Dev 23(7):781–783

    PubMed  CAS  PubMed Central  Google Scholar 

  137. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734

    PubMed  CAS  PubMed Central  Google Scholar 

  138. Wu H, Zhang Y (2011) Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 25(23):2436–2452

    PubMed  CAS  PubMed Central  Google Scholar 

  139. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705

    PubMed  CAS  Google Scholar 

  140. Tan M, Luo H, Lee S et al (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146(6):1016–1028

    PubMed  CAS  PubMed Central  Google Scholar 

  141. Barski A, Cuddapah S, Cui K et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129(4):823–837

    PubMed  CAS  Google Scholar 

  142. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6(8):597–610

    PubMed  CAS  Google Scholar 

  143. Wong KY, Huang X, Chim CS (2012) DNA methylation of microRNA genes in multiple myeloma. Carcinogenesis 33(9):1629–1638

    PubMed  CAS  Google Scholar 

  144. Dahl C, Guldberg P (2003) DNA methylation analysis techniques. Biogerontology 4(4):233–250

    PubMed  CAS  Google Scholar 

  145. Laird PW (2010) Principles and challenges of genome-wide DNA methylation analysis. Nat Rev Genet 11(3):191–203

    PubMed  CAS  Google Scholar 

  146. Shen L, Waterland RA (2007) Methods of DNA methylation analysis. Curr Opin Clin Nutr Metab Care 10(5):576–581

    PubMed  CAS  Google Scholar 

  147. Felsenfeld G, McGhee J (1982) Methylation and gene control. Nature 296(5858):602–603

    PubMed  CAS  Google Scholar 

  148. Eick D, Fritz HJ, Doerfler W (1983) Quantitative determination of 5-methylcytosine in DNA by reverse-phase high-performance liquid chromatography. Anal Biochem 135(1):165–171

    PubMed  CAS  Google Scholar 

  149. Frommer M, McDonald LE, Millar DS et al (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A 89(5):1827–1831

    PubMed  CAS  PubMed Central  Google Scholar 

  150. Hayatsu H, Shiraishi M, Negishi K (2008) Bisulfite modification for analysis of DNA methylation. Curr Protoc Nucleic Acid Chem Chapter 6:Unit 6.10

    PubMed  Google Scholar 

  151. Hayatsu H, Wataya Y, Kai K, Iida S (1970) Reaction of sodium bisulfite with uracil, cytosine, and their derivatives. Biochemistry 9(14):2858–2865

    PubMed  CAS  Google Scholar 

  152. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93(18):9821–9826

    PubMed  CAS  PubMed Central  Google Scholar 

  153. Xiong Z, Laird PW (1997) COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res 25(12):2532–2534

    PubMed  CAS  PubMed Central  Google Scholar 

  154. Gonzalgo ML, Jones PA (1997) Rapid quantitation of methylation differences at specific sites using methylation-sensitive single nucleotide primer extension (Ms-SNuPE). Nucleic Acids Res 25(12):2529–2531

    PubMed  CAS  PubMed Central  Google Scholar 

  155. Eads CA, Danenberg KD, Kawakami K et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28(8):E32

    PubMed  CAS  PubMed Central  Google Scholar 

  156. Colella S, Shen L, Baggerly KA, Issa JP, Krahe R (2003) Sensitive and quantitative universal pyrosequencing methylation analysis of CpG sites. Biotechniques 35(1):146–150

    PubMed  CAS  Google Scholar 

  157. Ronaghi M, Karamohamed S, Pettersson B, Uhlen M, Nyren P (1996) Real-time DNA sequencing using detection of pyrophosphate release. Anal Biochem 242(1):84–89

    PubMed  CAS  Google Scholar 

  158. Ehrich M, Nelson MR, Stanssens P et al (2005) Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A 102(44):15785–15790

    PubMed  CAS  PubMed Central  Google Scholar 

  159. Zilberman D, Henikoff S (2007) Genome-wide analysis of DNA methylation patterns. Development 134(22):3959–3965

    PubMed  CAS  Google Scholar 

  160. Kondo Y, Issa JP (2010) DNA methylation profiling in cancer. Expert Rev Mol Med 12:e23

    PubMed  Google Scholar 

  161. Zuo T, Tycko B, Liu TM, Lin JJ, Huang TH (2009) Methods in DNA methylation profiling. Epigenomics 1(2):331–345

    PubMed  CAS  PubMed Central  Google Scholar 

  162. Walker BA, Wardell CP, Chiecchio L et al (2011) Aberrant global methylation patterns affect the molecular pathogenesis and prognosis of multiple myeloma. Blood 117(2):553–562

    PubMed  CAS  Google Scholar 

  163. Amaral PP, Dinger ME, Mercer TR, Mattick JS (2008) The eukaryotic genome as an RNA machine. Science 319(5871):1787–1789

    PubMed  CAS  Google Scholar 

  164. Tsai HC, Li H, Van Neste L et al (2012) Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21(3):430–446

    PubMed  CAS  PubMed Central  Google Scholar 

  165. Lister R, Pelizzola M, Dowen RH et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315–322

    PubMed  CAS  PubMed Central  Google Scholar 

  166. Kim JH, Dhanasekaran SM, Prensner JR et al (2011) Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer. Genome Res 21(7):1028–1041

    PubMed  CAS  PubMed Central  Google Scholar 

  167. Ordway JM, Bedell JA, Citek RW et al (2006) Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis 27(12):2409–2423

    PubMed  CAS  Google Scholar 

  168. Oda M, Glass JL, Thompson RF et al (2009) High-resolution genome-wide cytosine methylation profiling with simultaneous copy number analysis and optimization for limited cell numbers. Nucleic Acids Res 37(12):3829–3839

    PubMed  CAS  PubMed Central  Google Scholar 

  169. Ruike Y, Imanaka Y, Sato F, Shimizu K, Tsujimoto G (2010) Genome-wide analysis of aberrant methylation in human breast cancer cells using methyl-DNA immunoprecipitation combined with high-throughput sequencing. BMC Genomics 11:137. doi:10.1186/1471-2164-11-137

    PubMed  PubMed Central  Google Scholar 

  170. Cheung HH, Lee TL, Davis AJ, Taft DH, Rennert OM, Chan WY (2010) Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. Br J Cancer 102(2):419–427

    PubMed  CAS  PubMed Central  Google Scholar 

  171. Bollati V, Fabris S, Pegoraro V et al (2009) Differential repetitive DNA methylation in multiple myeloma molecular subgroups. Carcinogenesis 30(8):1330–1335

    PubMed  CAS  Google Scholar 

  172. Chen G, Wang Y, Huang H 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

    PubMed  CAS  Google Scholar 

  173. 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

    PubMed  Google Scholar 

  174. Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG (2003) SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood 101(7):2784–2788

    PubMed  CAS  Google Scholar 

  175. Hatzimichael E, Dranitsaris G, Dasoula A et al (2009) Von Hippel-Lindau methylation status in patients with multiple myeloma: a potential predictive factor for the development of bone disease. Clin Lymphoma Myeloma 9(3):239–242

    PubMed  CAS  Google Scholar 

  176. Hodge DR, Peng B, Cherry JC et al (2005) Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation. Cancer Res 65(11):4673–4682

    PubMed  CAS  Google Scholar 

  177. Ng MH, Chung YF, Lo KW, Wickham NW, Lee JC, Huang DP (1997) Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood 89(7):2500–2506

    PubMed  CAS  Google Scholar 

  178. Seidl S, Ackermann J, Kaufmann H et al (2004) DNA-methylation analysis identifies the E-cadherin gene as a potential marker of disease progression in patients with monoclonal gammopathies. Cancer 100(12):2598–2606

    PubMed  CAS  Google Scholar 

  179. Tshuikina M, Jernberg-Wiklund H, Nilsson K, Oberg F (2008) Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma. Exp Hematol 36(12):1673–1681

    PubMed  CAS  Google Scholar 

  180. Mateos MV, Garcia-Sanz R, Lopez-Perez R et al (2002) Methylation is an inactivating mechanism of the p16 gene in multiple myeloma associated with high plasma cell proliferation and short survival. Br J Haematol 118(4):1034–1040

    PubMed  CAS  Google Scholar 

  181. Ribas C, Colleoni GW, Felix RS et al (2005) P16 gene methylation lacks correlation with angiogenesis and prognosis in multiple myeloma. Cancer Lett 222(2):247–254

    PubMed  CAS  Google Scholar 

  182. Braggio E, Maiolino A, Gouveia ME et al (2010) Methylation status of nine tumor suppressor genes in multiple myeloma. Int J Hematol 91(1):87–96

    PubMed  CAS  Google Scholar 

  183. Takada S, Morita K, Hayashi K et al (2005) Methylation status of fragile histidine triad (FHIT) gene and its clinical impact on prognosis of patients with multiple myeloma. Eur J Haematol 75(6):505–510

    PubMed  CAS  Google Scholar 

  184. Sharma A, Heuck CJ, Fazzari MJ et al (2010) DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer. Wiley Interdiscip Rev Syst Biol Med 2(6):654–669

    PubMed  CAS  Google Scholar 

  185. Brookes AJ (1999) The essence of SNPs. Gene 234(2):177–186

    PubMed  CAS  Google Scholar 

  186. Syvanen AC, Landegren U, Isaksson A, Gyllensten U, Brookes A (1999) First International SNP Meeting at Skokloster, Sweden, August 1998. Enthusiasm mixed with scepticism about single-nucleotide polymorphism markers for dissecting complex disorders. Eur J Hum Genet 7(1):98–101

    PubMed  CAS  Google Scholar 

  187. Moreaux J, Reme T, Leonard W et al (2013) Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors. Br J Cancer 109(3):676–685

    PubMed  CAS  PubMed Central  Google Scholar 

  188. Moreaux J, Reme T, Leonard W et al (2012) Development of gene expression-based score to predict sensitivity of multiple myeloma cells to DNA methylation inhibitors. Mol Cancer Ther 11(12):2685–2692

    PubMed  CAS  Google Scholar 

  189. Dick JE (2008) Stem cell concepts renew cancer research. Blood 112(13):4793–4807

    PubMed  CAS  Google Scholar 

  190. Matsui W, Wang Q, Barber JP et al (2008) Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68(1):190–197

    PubMed  CAS  PubMed Central  Google Scholar 

  191. Kalisky T, Quake SR (2011) Single-cell genomics. Nat Methods 8(4):311–314

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Genetics, Cell Biology and Development, University of Minnesota, Cancer Center, Minneapolis, MN, 55455, USA

    Amit Kumar Mitra, Holly Stessman & Brian Van Ness

  2. Signal Genetics and Myeloma Institute, University of Arkansas Medical Center, Little Rock, AK, USA

    John Shaughnessy

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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Mitra, A.K., Stessman, H., Shaughnessy, J., Van Ness, B. (2014). Profiling Bortezomib Resistance in Multiple Myeloma: Implications in Personalized Pharmacotherapy. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_5

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