Cytokines and signal transduction in multiple myeloma

Neoplastic Diseases of the Blood

Volumn , Issue , 2013, Pages 535-546

  Chauhan, Dharminder ^a   Anderson, Kenneth C ^a  

^a DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

Insulin like growth factor I; Interleukin 6; Multiple myeloma growth factors

Indexed keywords

EID: 84929544849     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-4614-3764-2_27     Document Type: Chapter

References (168)

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-20.
2. Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111:2521-6.
3. Ludwig H, Beksac M, Blade J, et al. Current multiple myeloma treatment strategies with novel agents: A European perspective. Oncologist. 2010;15:6-25.
4. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111: 2962-72.
5. Anderson KC. Targeted therapy of multiple myeloma based upon tumor-microenvironmental interactions. Exp Hematol. 2007;35: 155-62.
6. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332:83-5.
7. Anderson KC, Jones RM, Morimoto C, Leavitt P, Barut BA. Response patterns of purified myeloma cells to hematopoietic growth factors. Blood. 1989;73:1915-24.
8. Klein B, Zhang XG, Jourdan M, et al. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood. 1989;73:517-26.
9. Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood. 1993;82:3712-20.
10. Urashima M, Ogata A, Chauhan D, et al. Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood. 1996;88:2219-27.
11. Chauhan D, Uchiyama H, Akbarali Y, et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood. 1996;87:1104-12.
12. Barut BA, Zon LI, Cochran MK, et al. Role of interleukin 6 in the growth of myeloma-derived cell lines. Leuk Res. 1992;16:951-9.
13. Chauhan D, Pandey P, Ogata A, et al. Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. Oncogene. 1997;15:837-43.
14. Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J. Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol. 1995;162:248-55.
15. Klein B, Wijdenes J, Zhang XG, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood. 1991;78:1198-204.
16. Bataille R, Barlogie B, Lu ZY, et al. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood. 1995;86:685-91.
17. Sporeno E, Savino R, Ciapponi L, et al. Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. Blood. 1996;87:4510-9.
18. Suematsu S, Matsuda T, Aozasa K, et al. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA. 1989;86:7547-51.
19. Lattanzio G, Libert C, Aquilina M, et al. Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice. Am J Pathol. 1997;151:689-96.
20. Bataille R, Jourdan M, Zhang XG, et al. Serum levels of interleukin-6, a potent myeloma cell growth factor, as a reflection of disease severity in plasma cell dyscrasias. J Clin Invest. 1989;84:2008-11.
21. Barille S, Collette M, Bataille R, et al. Myeloma cells upregulate IL-6 but downregulate osteocalcin production by osteoblastic cells through cell to cell contact. Blood. 1995;86:3151-9.
22. Wen XY, Stewart AK, Sooknanan RR, et al. Identification of c-myc promoter-binding protein and X-box binding protein 1 as interleukin-6 target genes in human multiple myeloma cells. Int J Oncol. 1999;15:173-8.
23. Chauhan D, Li G, Auclair D, et al. Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays. Blood. 2003;101:3606-14.
24. Bagratuni T, Wu P, Gonzalez de Castro D, et al. XBP1s levels are implicated in the biology and outcome of myeloma mediating differential clinical outcomes to thalidomide-based treatments. Blood. 2010;116(2):250-3.
25. Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, Glimcher LH. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol. 2003;4:321-9.
26. Klein B, Tarte K, Jourdan M, et al. Survival and proliferation factors of normal and malignant plasma cells. Int J Hematol. 2003;78:106-13.
27. Wu KD, Orme LM, Shaughnessy Jr J, Jacobson J, Barlogie B, Moore MA. Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival. Blood. 2003;101:4982-9.
28. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell. 1994;76:253.
29. Ogata A, Chauhan D, Teoh G, et al. Interleukin-6 triggers cell growth via the ras-dependent mitogen-activated protein kinase cascade. J Immunol. 1997;159(5):2212-21.
30. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374:1-20.
31. Chauhan D, Anderson KC. Mechanisms of cell death and survival in multiple myeloma (MM): therapeutic implications. Apoptosis. 2003;8:337-43.
32. Li J, Favata M, Kelley JA, et al. INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support. Neoplasia. 2010;12:28-38.
33. Cirstea D, Hideshima T, Rodig S, et al. Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma. Mol Cancer Ther. 2010;9: 963-75.
34. Kim K, Kong SY, Fulciniti M, et al. Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. Br J Haematol. 2010;149(4):537-49.
35. Catlett-Falcone R, Landowski TH, Oshiro M, et al. Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10:105-15.
36. Derenne S, Monia B, Dean NM, et al. Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. Blood. 2002;100:194-9.
37. Neumann C, Zehentmaier G, Danhauser-Riedl S, Emmerich B, Hallek M. Interleukin-6 induces tyrosine phosphorylation of the Ras activating protein Shc, and its complex formation with Grb2 in the human multiple myeloma cell line LP-1. Eur J Immunol. 1996;26:379-84.
38. Hideshima T, Nakamura N, Chauhan D, Anderson KC. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene. 2001;20:5991-6000.
39. Hsu JH, Shi Y, Hu L, Fisher M, Franke TF, Lichtenstein A. Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses. Oncogene. 2002;21:1391-400.
40. Podar K, Tai YT, Cole CE, et al. Essential role of caveolae in interleukin-6-and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells. J Biol Chem. 2003;278:5794-801.
41. Ogata A, Chauhan D, Urashima M, Teoh G, Treon SP, Anderson KC. Blockade of mitogen-activated protein kinase cascade signaling in interleukin 6-independent multiple myeloma cells. Clin Cancer Res. 1997;3:1017-22.
42. Dai Y, Pei XY, Rahmani M, Conrad DH, Dent P, Grant S. Interruption of the NF-{kappa}b pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. Blood. 2003;103(7):2761-70.
43. Alas S, Bonavida B. Inhibition of constitutive STAT3 activity sensitizes resistant Non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res. 2003;9:316-26.
44. Hu L, Shi Y, Hsu JH, Gera J, Van Ness B, Lichtenstein A. Downstream effectors of oncogenic ras in multiple myeloma cells. Blood. 2003;101:3126-35.
45. Chauhan D, Velankar M, Brahmandam M, et al. A novel Bcl-2/ Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene. 2007;26:2374-80.
46. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: A workshop report. Cancer Res. 2004;64: 1546-58.
47. Chng WJ, Gonzalez-Paz N, Price-Troska T, et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia. 2008;22:2280-4.
48. Bezieau S, Devilder MC, Avet-Loiseau H, et al. High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat. 2001;18:212-24.
49. Crowder C, Kopantzev E, Williams K, Lengel C, Miki T, Rudikoff S. An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth. Oncogene. 2003;22:649-59.
50. Chesi M, Bergsagel PL, Kuehl WM. The enigma of ectopic expression of FGFR3 in multiple myeloma: A critical initiating event or just a target for mutational activation during tumor progression. Curr Opin Hematol. 2002;9:288-93.
51. Winkler JM, Greipp P, Fonseca R. t(4;14)(p16.3;q32) is strongly associated with a shorter survival in myeloma patients. Br J Haematol. 2003;120:170-1.
52. Kuehl WM, Brents LA, Chesi M, Huppi K, Bergsagel PL. Dysregulation of c-myc in multiple myeloma. Curr Top Microbiol Immunol. 1997;224:277-82.
53. Chesi M, Bergsagel PL, Shonukan OO, et al. Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma. Blood. 1998;91:4457-63.
54. Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene. 2001;20:5611-22.
55. Shaughnessy Jr J, Gabrea A, Qi Y, et al. Cyclin D3 at 6p21 is dysregulated by recurrent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood. 2001;98:217-23.
56. Rasmussen T, Theilgaard-Monch K, Hudlebusch HR, Lodahl M, Johnsen HE, Dahl IM. Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entities. Br J Haematol. 2003;123:253-62.
57. Urashima M, Teoh G, Ogata A, et al. Role of CDK4 and p16 INK4A in interleukin-6-mediated growth of multiple myeloma. Leukemia. 1997;11:1957-63.
58. Hardin J, MacLeod S, Grigorieva I, et al. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood. 1994;84: 3063-70.
59. Chauhan D, Kharbanda S, Ogata A, et al. Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells. Blood. 1997;89:227-34.
60. Chauhan D, Pandey P, Ogata A, et al. Cytochrome-c dependent and independent induction of apoptosis in multiple myeloma cells. J Biol Chem. 1997;272:29995-7.
61. Xu F, Sharma S, Gardner S, et al. Interleukin-6 induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway. Blood. 1998;92:241-51.
62. Chauhan D, Pandey P, Hideshima T, et al. SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem. 2000;275: 27845-50.
63. Bossy-Wetzel E, Green DR. Apoptosis: checkpoint at the mitochondrial frontier. Mutat Res. 1999;434:243-51.
64. Ferri KF, Kroemer G. Mitochondria-The suicide organelles. Bioessays. 2001;23:111-5.
65. Chauhan D, Hideshima T, Rosen S, Reed JC, Kharbanda S, Anderson KC. Apaf-1/cytochrome c-independent and Smacdependent induction of apoptosis in multiple myeloma (MM) cells. J Biol Chem. 2001;276:24453-6.
66. Chauhan D, Li G, Sattler M, et al. Superoxide-dependent and-independent mitochondrial signaling during apoptosis in multiple myeloma cells. Oncogene. 2003;22:6296-300.
67. Ogata A, Nishimoto N, Shima Y, Yoshizaki K, Kishimoto T. Inhibitory effect of All-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction. Blood. 1994;84:3040-6.
68. Kreitman R, Siegall CB, Fitzgerald DJP, et al. Interleukin-6 fused to mutant form of pseudomonas exotoxin kills malignant cells form patients with multiple myeloma. Blood. 1992;79:1775-80.
69. Jelinek DF, Witzig TE, Arendt BK. A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. J Immunol. 1997;159:487-96.
70. Vanderkerken K, Asosingh K, Braet F, Van Riet I, Van Camp B. Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells. Blood. 1999;93:235-41.
71. Ge NL, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood. 2000;96:2856-61.
72. Xu F, Gardner A, Tu Y, Michl P, Prager D, Lichtenstein A. Multiple myeloma cells are protected against dexamethasone-induced apoptosis by insulin-like growth factors. Br J Haematol. 1997;97: 429-40.
73. Descamps G, Gomez-Bougie P, Venot C, Moreau P, Bataille R, Amiot M. A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances Bortezomib-induced apoptosis in myeloma cells lacking CD45. Br J Cancer. 2009;100:366-9.
74. Menoret E, Maiga S, Descamps G, et al. IL-21 stimulates human myeloma cell growth through an autocrine IGF-1 loop. J Immunol. 2008;181:6837-42.
75. Tai YT, Podar K, Catley L, et al. Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3 '-kinase/ AKT signaling. Cancer Res. 2003;63:5850-8.
76. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell. 2004;5:221-30.
77. Qiang YW, Kopantzev E, Rudikoff S. Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. Blood. 2002;99:4138-46.
78. De Bruyne E, Bos TJ, Schuit F, et al. IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms. Blood. 2010;115:2430-40.
79. Mitsiades CS, Mitsiades N, Poulaki V, et al. 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. 2002;21:5673-83.
80. Tu Y, Gardner A, Lichtenstein A. The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res. 2000;60:6763-70.
81. Abroun S, Ishikawa H, Tsuyama N, et al. Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor alpha [corrected]. Blood. 2004;103:2291-8.
82. Akiyama M, Hideshima T, Hayashi T, et al. Nuclear factor-kappaB p65 mediates tumor necrosis factor alpha-induced nuclear translocation of telomerase reverse transcriptase protein. Cancer Res. 2003;63:18-21.
83. Sprynski AC, Hose D, Caillot L, et al. The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood. 2009;113: 4614-26.
84. Chng WJ, Gualberto A, Fonseca R. IGF-1R is overexpressed in poor-prognostic subtypes of multiple myeloma. Leukemia. 2006;20:174-6.
85. Di Raimondo F, Azzaro MP, Palumbo G, et al. Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood. Haematologica. 2000;85:800-5.
86. Rajkumar SV, Witzig TE. A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev. 2000;26:351-62.
87. Xu JL, Lai R, Kinoshita T, Nakashima N, Nagasaka T. Proliferation, apoptosis, and intratumoral vascularity in multiple myeloma: correlation with the clinical stage and cytological grade. J Clin Pathol. 2002;55:530-4.
88. Podar K, Tai YT, Davies FE, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood. 2001;98:428-35.
89. Podar K, Tai YT, Lin BK, et al. Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin-and phosphatidylinositol 3-kinase-dependent PKCalpha activation. J Biol Chem. 2002;277:7875-81.
90. Dankar B, Padro T, Leo R, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood. 2000;95:2630-336.
91. Giuliani N, Lunghi P, Morandi F, et al. Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis. Leukemia. 2004;18:628-35.
92. Podar K, Anderson KC. Inhibition of VEGF signaling pathways in multiple myeloma and other malignancies. Cell Cycle. 2007;6:538-42.
93. Hurt EM, Wiestner A, Rosenwald A, et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell. 2004;5:191-9.
94. Chauhan D, Singh AV, Brahmandam M, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: A therapeutic target. Cancer Cell. 2009;16:309-23.
95. Lin B, Podar K, Gupta D, et al. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2002;62:5019-26.
96. Yang DH, Park JS, Jin CJ, et al. The dysfunction and abnormal signaling pathway of dendritic cells loaded by tumor antigen can be overcome by neutralizing VEGF in multiple myeloma. Leuk Res. 2009;33:665-70.
97. Vacca A, Ribatti D, Presta M, et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood. 1999;93:3064-73.
98. Bisping G, Wenning D, Kropff M, et al. Bortezomib, dexamethasone, andfibroblast growth factor receptor 3-specific tyrosine kinase inhibitor in t(4;14) myeloma. Clin Cancer Res. 2009;15:520-31.
99. Urashima M, Ogata A, Chauhan D, et al. Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. Blood. 1996;87:1928-38.
100. Kyrtsonis MC, Repa C, Dedoussis GV, et al. Serum transforming growth factor-beta 1 is related to the degree of immunoparesis in patients with multiple myeloma. Med Oncol. 1998;15:124-8.
101. Urba ska-Rys H, Wierzbowska A, Robak T. Circulating angiogenic cytokines in multiple myeloma and related disorders. Eur Cytokine Netw. 2003;14:40-51.
102. Hayashi T, Hideshima T, Nguyen AN, et al. Transforming growth factor beta receptor I kinase inhibitor down-regulates cytokine secretion and multiple myeloma cell growth in the bone marrow microenvironment. Clin Cancer Res. 2004;10:7540-6.
103. Kawamura C, Kizaki M, Yamato K, et al. Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood. 2000;96:2005-11.
104. Thompson MA, Witzig TE, Kumar S, et al. Plasma levels of tumour necrosis factor alpha and interleukin-6 predict progression-free survival following thalidomide therapy in patients with previously untreated multiple myeloma. Br J Haematol. 2003;123:305-8.
105. Alexandrakis MG, Passam FH, Sfiridaki K, et al. Interleukin-18 in multiple myeloma patients: serum levels in relation to response to treatment and survival. Leuk Res. 2004;28:259-66.
106. Hideshima T, Chauhan D, Schlossman R, Richardson P, Anderson KC. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene. 2001;20:4519-27.
107. Bharti AC, Donato N, Singh S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and Ikappa Balpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood. 2003;101:1053-62.
108. Kadar K, Kovacs M, Karadi I, et al. Polymorphisms of TNF-alpha and LT-alpha genes in multiple myeloma. Leuk Res. 2008;32:1499-504.
109. Johrer K, Janke K, Krugmann J, Fiegl M, Greil R. Transendothelial migration of myeloma cells is increased by tumor necrosis factor (TNF)-alpha via TNF receptor 2 and autocrine up-regulation of MCP-1. Clin Cancer Res. 2004;10:1901-10.
110. Tai YT, Podar K, Mitsiades N, et al. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/ AKT/NF-kappa B signaling. Blood. 2003;101:2762-9.
111. Hussein M, Berenson JR, Niesvizky R, et al. A phase 1 multidose study of dacetuzumab (SGN-40; humanized anti-CD40 mAb) in patients with multiple myeloma. Haematologica. 2010;95(5): 845-8.
112. Tai YT, Li X, Tong X, et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res. 2005;65:5898-906.
113. Alsayed Y, Ngo H, Runnels J, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood. 2007;109:2708-17.
114. Mackay F, Schneider P, Rennert P, Browning J. BAFF AND APRIL: A tutorial on B cell survival. Annu Rev Immunol. 2003;21:231-64.
115. Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: A mechanism for growth and survival. Blood. 2004;103:689-94.
116. Moreaux J, Hose D, Jourdan M, et al. TACI expression is associated with a mature bone marrow plasma cell signature and C-MAF overexpression in human myeloma cell lines. Haematologica. 2007;92:803-11.
117. Moreaux J, Sprynski AC, Dillon SR, et al. APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur J Haematol. 2009;83: 119-29.
118. Kukreja A, Hutchinson A, Dhodapkar K, et al. Enhancement of clonogenicity of human multiple myeloma by dendritic cells. J Exp Med. 2006;203:1859-65.
119. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol. 2007;20:613-24.
120. Vallet S, Mukherjee S, Vaghela N, et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA. 2010;107:5124-9.
121. Vanderkerken K, De Leenheer E, Shipman C, et al. Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. Cancer Res. 2003;63: 287-9.
122. Sordillo EM, Pearse RN. RANK-Fc: A therapeutic antagonist for RANK-L in myeloma. Cancer. 2003;97:802-12.
123. Terpos E, Efstathiou E, Christoulas D, Roussou M, Katodritou E, Dimopoulos MA. RANKL inhibition: clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases. Expert Opin Biol Ther. 2009;9:465-79.
124. Qiang YW, Chen Y, Stephens O, et al. Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: A potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood. 2008;112:196-207.
125. Vallet S, Raje N, Ishitsuka K, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood. 2007;110(10): 3744-52.
126. Drake MT, Rajkumar SV. Effects of bortezomib on bone disease in multiple myeloma. Am J Hematol. 2009;84:1-2.
127. Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483-94.
128. Qiang YW, Shaughnessy Jr JD, Yaccoby S. Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. Blood. 2008;112:374-82.
129. Derksen PW, Tjin E, Meijer HP, et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci USA. 2004;101(16):6122-7.
130. Niida A, Hiroko T, Kasai M, et al. DKK1, a negative regulator of Wnt signaling, is a target of the beta-catenin/TCF pathway. Oncogene. 2004;23:8520-6.
131. Durie BG, Van Ness B, Ramos C, et al. Genetic polymorphisms of EPHX1, Gsk3beta, TNFSF8 and myeloma cell DKK-1 expression linked to bone disease in myeloma. Leukemia. 2009;23:1913-9.
132. Zimmermann P, David G. The syndecans, tuners of transmembrane signaling. FASEB J. 1999;13(Suppl):S91-S100.
133. Wang YD, De Vos J, Jourdan M, et al. Cooperation between heparin-binding EGF-like growth factor and interleukin-6 in promoting the growth of human myeloma cells. Oncogene. 2002;21:2584-92.
134. Bergui L, Schena M, Gaidano G, et al. Interleukin 3 and interleukin 6 synergistically promote the proliferation and differentiation of malignant plasma cell precursors in multiple myeloma. J Exp Med. 1989;170:613-8.
135. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585-98.
136. Lee JW, Chung HY, Ehrlich LA, et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood. 2004;103:2308-15.
137. Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J Exp Med. 1997;185:1101-11.
138. Chauhan D, Kharbanda SM, Ogata A, et al. Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. J Exp Med. 1995;182:1801-6.
139. Zhang XG, Bataille R, Jourdan M, et al. Granulocyte-macrophage colony-stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells. Blood. 1990;76:2599.
140. Anderson KC, Morimoto C, Paul SR, et al. Interleukin-11 promotes accessory cell dependent B cell differentiation in man. Blood. 1992;80:2797-804.
141. Paul SD, Barut BA, Cochran MA, Anderson KC. Lack of a role of interleukin-11 in the growth of multiple myeloma. Leuk Res. 1992;16:247-52.
142. Lu ZY, Zhang XG, Rodriguez C, et al. Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells. Blood. 1995;85:2521.
143. Hjorth-Hansen H, Waage A, Borset M. Interleukin-15 blocks apoptosis and induces proliferation of the human myeloma cell line OH-2 and freshly isolated myeloma cells. Br J Haematol. 1999;106:28-34.
144. Brenne AT, Baade Ro T, Waage A, Sundan A, Borset M, Hjorth-Hansen H. Interleukin-21 is a growth and survival factor for human myeloma cells. Blood. 2002;99:3756-62.
145. Tinhofer I, Marschitz I, Henn T, Egle A, Greil R. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood. 2000;95:610-8.
146. Anargyrou K, Terpos E, Vassilakopoulos TP, et al. Normalization of the serum angiopoietin-1 to angiopoietin-2 ratio reflects response in refractory/resistant multiple myeloma patients treated with bortezomib. Haematologica. 2008;93:451-4.
147. Prabhala RH, Pelluru D, Fulciniti M, et al. Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood. 2010;115(26): 5385-92.
148. Martin SK, Diamond P, Williams SA, et al. Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica. 2010;95:776-84.
149. Hideshima T, Neri P, Tassone P, et al. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res. 2006;12:5887-94.
150. Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003;63:6174-7.
151. Hideshima T, Mitsiades C, Ikeda H, et al. A proto-oncogene Bcl-6 is upregulated in the bone marrow microenvironment in multiple myeloma cells. Blood. 2010;115(18):3772-5.
152. Chauhan D, Li G, Podar K, et al. A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Res. 2005;65:8350-8.
153. Chauhan D, Li G, Hideshima T, et al. Blockade of ubiquitinconjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341. Oncogene. 2004;23: 3597-602.
154. Chauhan D, Li G, Hideshima T, et al. JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. J Biol Chem. 2003;278:17593-6.
155. Podar K, Gouill SL, Zhang J, et al. A pivotal role for Mcl-1 in Bortezomib-induced apoptosis. Oncogene. 2007;27(6): 721-31.
156. Podar K, Raab MS, Zhang J, et al. Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl). Blood. 2007;109:1669-77.
157. Chauhan D, Neri P, Velankar M, et al. Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood. 2007;109:1220-7.
158. Hideshima T, Catley L, Yasui H, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107:4053-62.
159. Tong WG, Chen R, Plunkett W, et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 2010;28(18): 3015-22.
160. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA. 2002;99:14374-9.
161. Chauhan D, Catley L, Hideshima T, et al. 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells. Blood. 2002;100:2187-94.
162. Chauhan D, Li G, Auclair D, et al. 2-Methoxyestardiol and bortezomib/ proteasome-inhibitor overcome dexamethasone-resistance in multiple myeloma cells by modulating Heat Shock Protein-27. Apoptosis. 2004;9:149-55.
163. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 2004;101:540-5.
164. Chauhan D, Auclair D, Robinson EK, et al. Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. Oncogene. 2002;21:1346-58.
165. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA. 2005;102:8567-72.
166. Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and {alpha}-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006;108:3441-49.
167. Jagannath S, Dimopoulos MA, Lonial S. Combined proteasome and histone deacetylase inhibition: A promising synergy for patients with relapsed/refractory multiple myeloma. Leuk Res. 2010;34(9):1111-8.
168. Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood. 2004;104:4188-93.