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Bone marrow microenvironment and the identification of new targets for myeloma therapy

Abstract

The development of multiple myeloma (MM) is a complex multi-step process involving both early and late genetic changes in the tumor cell as well as selective supportive conditions by the bone marrow (BM) microenvironment. Indeed, it is now well established that MM cell-induced disruption of the BM homeostasis between the highly organized cellular and extracellular compartments supports MM cell proliferation, survival, migration and drug resistance through activation of various signaling (for example, PI3K/Akt, JAK/Stat-, Raf/MEK/MAPK-, NFκB- and Wnt-) pathways. Based on our enhanced understanding of the functional importance of the MM BM microenvironment and its inter-relation with the MM cell resulting in homing, seeding, proliferation and survival, new molecular targets have been identified and derived treatment regimens in MM have already changed fundamentally during recent years. These agents include thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, which mediate tumor cytotoxicity in the BM milieu. Ongoing studies are further delineating MM pathogenesis in the BM to enhance cytotoxicity, avoid drug resistance and improve patient outcome.

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References

  1. Fonseca R, Bailey RJ, Ahmann GJ, Rajkumar SV, Hoyer JD, Lust JA et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002; 100: 1417–1424.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006; 9: 313–325.

    Article  CAS  PubMed  Google Scholar 

  5. Hazlehurst LA, Landowski TH, Dalton WS . Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene 2003; 22: 7396–7402.

    CAS  PubMed  Google Scholar 

  6. 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: 585–598.

    CAS  PubMed  Google Scholar 

  7. Tai YT, Dillon M, Song W, Leiba M, Li XF, Burger P et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008; 112: 1329–1337, e-pub ahead of print.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sekimoto E, Ozaki S, Ohshima T, Shibata H, Hashimoto T, Abe M et al. A single-chain Fv diabody against human leukocyte antigen-A molecules specifically induces myeloma cell death in the bone marrow environment. Cancer Res 2007; 67: 1184–1192.

    CAS  PubMed  Google Scholar 

  9. Yang J, Qian J, Wezeman M, Wang S, Lin P, Wang M et al. Targeting beta2-microglobulin for induction of tumor apoptosis n human hematological malignancies. Cancer Cell 2006; 10: 295–307.

    CAS  PubMed  Google Scholar 

  10. Klein B . Cytokine, cytokine receptors, transduction signals, and oncogenes in human multiple myeloma. Semin Hematol 1995; 32: 4–19.

    CAS  PubMed  Google Scholar 

  11. Anderson KC, Lust JA . Role of cytokines in multiple myeloma. Semin Hematol 1999; 36 (1 Suppl 3): 14–20.

    CAS  PubMed  Google Scholar 

  12. Podar K, Hideshima T, Chauhan D, Anderson KC . Targeting signalling pathways for the treatment of multiple myeloma. Expert Opin Ther Targets 2005; 9: 359–381.

    CAS  PubMed  Google Scholar 

  13. Beaupre DM, Cepero E, Obeng EA, Boise LH, Lichtenheld MG . R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. Mol Cancer Ther 2004; 3: 179–186.

    CAS  PubMed  Google Scholar 

  14. Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004; 103: 3271–3277.

    CAS  PubMed  Google Scholar 

  15. David E, Schafer-Hales K, Marcus AI, Kaufman JL, Lonial S . Combination of Bortezomib with Tipifarnib (R115777) Induces Synergistic Myeloma Cell Apoptosis Via Down-Regulation of HDAC6 and Inhibition of Aggresome Formation. Blood 2007; ASH Annual Meeting Abstracts (110, abstract #1520).

  16. Armand JP, Burnett AK, Drach J, Harousseau JL, Lowenberg B, San Miguel J . The emerging role of targeted therapy for hematologic malignancies: update on bortezomib and tipifarnib. Oncologist 2007; 12: 281–290.

    CAS  PubMed  Google Scholar 

  17. Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF et al. Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood 2007; 110: 1656–1663.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Chauhan D et al. Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma. Br J Haematol 2007; 139: 55–63.

    CAS  PubMed  Google Scholar 

  19. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C et al. Perifosine, an oral bioactive novel alkyl-phospholipid, inhibits Akt and induces in vitro and In vivo cytotoxicity in human multiple myeloma (MM) cells. Blood 2005; 106 (11 (abstract #250)): 128.

    Google Scholar 

  20. Hideshima T, Catley L, Raje N, Chauhan D, Podar K, Mitsiades C et al. Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br J Haematol 2007; 138: 783–791.

    CAS  PubMed  Google Scholar 

  21. Gajate C, Mollinedo F . Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 2007; 109: 711–719.

    CAS  PubMed  Google Scholar 

  22. David E, Sinha R, Kaufman JL, Lonial S . Perifosine induces DR4/DR5 expression leading to apoptosis that can be enhanced with exogenous TRAIL, and blocked with strategies directed at DR4/DR5 inhibition. Blood 2006; 108, abstract #3446 (ASH Annual Meeting Abstracts).

  23. De P, Peng Q, Dey N, McDermitt B, Peng X, Garlich J et al. A vascular targeted pan PI-3 kinase inhibitor, SF1126 with activity against multiple myeloma in vivo. Blood 2006, (108 abstract #244).

  24. McMillin DW, Negri J, Delmore J, Hayden P, Mitsiades N, Richardson PG et al. Anti-myeloma activity of selective PI-3K/PDK/mTOR inhibitor BEZ235. Blood 2007; 110, abstract #1185(ASH annual meeting abstracts).

  25. Bharti AC, Shishodia S, Reuben JM, Weber D, Alexanian R, Raj-Vadhan S et al. Nuclear factor-kappaB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis. Blood 2004; 103: 3175–3184.

    CAS  PubMed  Google Scholar 

  26. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10: 105–115.

    Article  CAS  PubMed  Google Scholar 

  27. Bharti AC, Donato N, Aggarwal BB . Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 2003; 171: 3863–3871.

    CAS  PubMed  Google Scholar 

  28. Amit-Vazina M, Shishodia S, Harris D, Van Q, Wang M, Weber D et al. Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells. Br J Cancer 2005; 93: 70–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamasaki M, Hideshima T, Tassone P, Neri P, Ishitsuka K, Yasui H et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro .decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo. Blood 2005; 105: 4470–4476.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. De Vos J, Jourdan M, Tarte K, Jasmin C, Klein B . JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. Br J Haematol 2000; 109: 823–828.

    CAS  PubMed  Google Scholar 

  31. Pedranzini L, Dechow T, Berishaj M, Comenzo R, Zhou P, Azare J et al. Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res 2006; 66: 9714–9721.

    CAS  PubMed  Google Scholar 

  32. 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: 316–326.

    CAS  PubMed  Google Scholar 

  33. Chatterjee M, Stuhmer T, Herrmann P, Bommert K, Dorken B, Bargou RC . Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells. Blood 2004; 104: 3712–3721.

    CAS  PubMed  Google Scholar 

  34. Gilmore TD . Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 2006; 25: 6680–6684.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12: 131–144.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 1996; 87: 1104–1112.

    CAS  PubMed  Google Scholar 

  38. Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res 2006; 66: 6675–6682.

    CAS  PubMed  Google Scholar 

  39. Gilmore TD, Herscovitch M . Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 2006; 25: 6887–6899.

    CAS  PubMed  Google Scholar 

  40. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 16639–16647.

    CAS  PubMed  Google Scholar 

  41. Hideshima T, Neri P, Tassone P, Yasui H, Ishitsuka K, Raje N et al. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Clin Cancer Res 2006; 12: 5887–5894.

    CAS  PubMed  Google Scholar 

  42. Sanda T, Iida S, Ogura H, Asamitsu K, Murata T, Bacon KB et al. Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor. Clin Cancer Res 2005; 11: 1974–1982.

    CAS  PubMed  Google Scholar 

  43. Derksen PW, Tjin E, Meijer HP, Klok MD, MacGillavry HD, van Oers MH et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc Natl Acad Sci USA 2004; 101: 6122–6127.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chim CS, Pang R, Fung TK, Choi CL, Liang R . Epigenetic dysregulation of Wnt signaling pathway in multiple myeloma. Leukemia 2007; 21: 2527–2536.

    CAS  PubMed  Google Scholar 

  45. Kobune M, Chiba H, Kato J, Kato K, Nakamura K, Kawano Y et al. Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism. Mol Cancer Ther 2007; 6: 1774–1784.

    CAS  PubMed  Google Scholar 

  46. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B 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: 2483–2494.

    CAS  PubMed  Google Scholar 

  47. Sukhdeo K, Mani M, Zhang Y, Dutta J, Yasui H, Rooney MD et al. Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 7516–7521.

    PubMed  PubMed Central  Google Scholar 

  48. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004; 5: 91–102.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. Urashima M, Chauhan D, Hatziyanni M, Ogata A, Hollenbaugh D, Aruffo A et al. CD40 ligand triggers interleukin-6 mediated B cell differentiation. Leuk Res 1996; 20: 507–515.

    CAS  PubMed  Google Scholar 

  51. Tai YT, Catley LP, Mitsiades CS, Burger R, Podar K, Shringpaure R et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res 2004; 64: 2846–2852.

    CAS  PubMed  Google Scholar 

  52. Tai YT, Li X, Tong X, Santos D, Otsuki T, Catley L et al. Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. Cancer Res 2005; 65: 5898–5906.

    CAS  PubMed  Google Scholar 

  53. Radtke F, Wilson A, Ernst B, MacDonald HR . The role of Notch signaling during hematopoietic lineage commitment. Immunol Rev 2002; 187: 65–74.

    CAS  PubMed  Google Scholar 

  54. Radtke F, Raj K . The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 2003; 3: 756–767.

    CAS  PubMed  Google Scholar 

  55. Cheng P, Nefedova Y, Miele L, Osborne BA, Gabrilovich D . Notch signaling is necessary but not sufficient for differentiation of dendritic cells. Blood 2003; 102: 3980–3988.

    CAS  PubMed  Google Scholar 

  56. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI . Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004; 103: 3503–3510.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  58. Jundt F, Probsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood 2004; 103: 3511–3515.

    CAS  PubMed  Google Scholar 

  59. Zweidler-McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC et al. Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 2005; 106: 3898–3906.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zdzisinska B, Walter-Croneck A, Kandefer-Szerszen M . Matrix metalloproteinases-1 and -2, and tissue inhibitor of metalloproteinase-2 production is abnormal in bone marrow stromal cells of multiple myeloma patients. Leuk Res 2008; 32: 1763–1769.

    CAS  PubMed  Google Scholar 

  61. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332–2336.

    CAS  PubMed  Google Scholar 

  62. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 4048–4053.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008; 68: 190–197.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Scadden DT . The stem-cell niche as an entity of action. Nature 2006; 441: 1075–1079.

    CAS  PubMed  Google Scholar 

  65. Wilson A, Trumpp A . Bone-marrow haematopoietic-stem-cell niches. Nat Rev 2006; 6: 93–106.

    CAS  Google Scholar 

  66. Yin T, Li L . The stem cell niches in bone. J Clin Invest 2006; 116: 1195–1201.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mariani S, Coscia M, Even J, Peola S, Foglietta M, Boccadoro M et al. Severe and long-lasting disruption of T-cell receptor diversity in human myeloma after high-dose chemotherapy and autologous peripheral blood progenitor cell infusion. Br J Haematol 2001; 113: 1051–1059.

    CAS  PubMed  Google Scholar 

  68. Massaia M, Bianchi A, Attisano C, Peola S, Redoglia V, Dianzani U et al. Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex. Blood 1991; 78: 1770–1780.

    CAS  PubMed  Google Scholar 

  69. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.

    CAS  PubMed  Google Scholar 

  70. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98: 210–216.

    CAS  PubMed  Google Scholar 

  71. Chang DH, Osman K, Connolly J, Kukreja A, Krasovsky J, Pack M et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med 2005; 201: 1503–1517.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Dhodapkar MV, Geller MD, Chang DH, Shimizu K, Fujii S, Dhodapkar KM et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med 2003; 197: 1667–1676.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 2002; 100: 230–237.

    CAS  PubMed  Google Scholar 

  74. Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood 2001; 98: 2992–2998.

    CAS  PubMed  Google Scholar 

  75. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996; 2: 1096–1103.

    CAS  PubMed  Google Scholar 

  76. Xie J, Wang Y, Freeman III ME, Barlogie B, Yi Q . Beta 2-microglobulin as a negative regulator of the immune system: high concentrations of the protein inhibit in vitro generation of functional dendritic cells. Blood 2003; 101: 4005–4012.

    CAS  PubMed  Google Scholar 

  77. Kukreja A, Hutchinson A, Dhodapkar K, Mazumder A, Vesole D, Angitapalli R et al. Enhancement of clonogenicity of human multiple myeloma by dendritic cells. J Exp Med 2006; 203: 1859–1865.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV . Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 2007; 109: 4839–4845.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kukreja A, Hutchinson A, Mazumder A, Vesole D, Angitapalli R, Jagannath S et al. Bortezomib disrupts tumour-dendritic cell interactions in myeloma and lymphoma: therapeutic implications. Br J Haematol 2007; 136: 106–110.

    CAS  PubMed  Google Scholar 

  80. Bae J, Mitsiades C, Tai YT, Bertheau R, Shammas M, Batchu RB et al. Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell. J Immunol 2007; 178: 7730–7737.

    CAS  PubMed  Google Scholar 

  81. Heissig B, Ohki Y, Sato Y, Rafii S, Werb Z, Hattori K . A role for niches in hematopoietic cell development. Hematology 2005; 10: 247–253.

    CAS  PubMed  Google Scholar 

  82. Kopp HG, Avecilla ST, Hooper AT, Rafii S . The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 2005; 20: 349–356.

    CAS  Google Scholar 

  83. Podar K, Anderson KC . The pathophysiological role of VEGF in hematological malignancies: therapeutic implications. Blood 2005; 105: 1383–1395.

    CAS  PubMed  Google Scholar 

  84. Zhang H, Vakil V, Braunstein M, Smith EL, Maroney J, Chen L et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood 2005; 105: 3286–3294.

    CAS  PubMed  Google Scholar 

  85. de Bont ES, Guikema JE, Scherpen F, Meeuwsen T, Kamps WA, Vellenga E et al. Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma. Cancer Res 2001; 61: 7654–7659.

    CAS  PubMed  Google Scholar 

  86. Scavelli C, Nico B, Cirulli T, Ria R, Di Pietro G, Mangieri D et al. Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene 2008; 27: 663–674.

    CAS  PubMed  Google Scholar 

  87. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 2006; 25: 4257–4266.

    CAS  PubMed  Google Scholar 

  88. Jakob C, Sterz J, Zavrski I, Heider U, Kleeberg L, Fleissner C et al. Angiogenesis in multiple myeloma. Eur J Cancer 2006; 42: 1581–1590.

    CAS  PubMed  Google Scholar 

  89. Folkman J . Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 2007; 6: 273–286.

    CAS  PubMed  Google Scholar 

  90. Podar K, Anderson KC . Inhibition of VEGF signaling pathways in multiple myeloma and other malignancies. Cell Cycle 2007; 6: 538–542.

    CAS  PubMed  Google Scholar 

  91. Giuliani N, Rizzoli V, Roodman GD . Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood 2006; 108: 3992–3996.

    CAS  PubMed  Google Scholar 

  92. Esteve FR, Roodman GD . Pathophysiology of myeloma bone disease. Best pract res 2007; 20: 613–624.

    CAS  Google Scholar 

  93. Terpos E, Sezer O, Croucher P, Dimopoulos MA . Myeloma bone disease and proteasome inhibition therapies. Blood 2007; 110: 1098–1104.

    CAS  PubMed  Google Scholar 

  94. Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Oshima T, Abe M, Asano J, Hara T, Kitazoe K, Sekimoto E et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 2005; 106: 3160–3165.

    CAS  PubMed  Google Scholar 

  96. Berenson JR . Bone disease in myeloma. Curr Treat Options Oncol 2001; 2: 271–283.

    CAS  PubMed  Google Scholar 

  97. Body JJ, Greipp P, Coleman RE, Facon T, Geurs F, Fermand JP et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003; 97 (3 Suppl): 887–892.

    PubMed  Google Scholar 

  98. Feng R, Oton A, Mapara MY, Anderson G, Belani C, Lentzsch S . The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. Br J Haematol 2007; 139: 385–397.

    CAS  PubMed  Google Scholar 

  99. Boissy P, Andersen TL, Abdallah BM, Kassem M, Plesner T, Delaisse JM . Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 2005; 65: 9943–9952.

    CAS  PubMed  Google Scholar 

  100. Vallet S, Raje N, Ishitsuka K, Hideshima T, Podar K, Chhetri S et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood 2007; 110: 3744–3752.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Feng R, Anderson G, Xiao G, Elliott G, Leoni L, Mapara MY et al. SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-kappaB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth. Blood 2007; 109: 2130–2138.

    CAS  PubMed  Google Scholar 

  102. Anderson G, Gries M, Kurihara N, Honjo T, Anderson J, Donnenberg V et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood 2006; 107: 3098–3105.

    CAS  PubMed  Google Scholar 

  103. von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M et al. Bortezomib inhibits human osteoclastogenesis. Leukemia 2007; 21: 2025–2034.

    CAS  PubMed  Google Scholar 

  104. Heider U, Kaiser M, Muller C, Jakob C, Zavrski I, Schulz CO et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol 2006; 77: 233–238.

    CAS  PubMed  Google Scholar 

  105. Corre J, Mahtouk K, Attal M, Gadelorge M, Huynh A, Fleury-Cappellesso S et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia 2007; 21: 1079–1088.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Arnulf B, Lecourt S, Soulier J, Ternaux B, Lacassagne MN, Crinquette A et al. Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia 2007; 21: 158–163.

    CAS  PubMed  Google Scholar 

  107. Mukherjee S, Raje N, Schoonmaker JA, Liu JC, Hideshima T, Wein MN et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest 2008; 118: 491–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood 2007; 110: 334–338.

    CAS  PubMed  Google Scholar 

  109. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–1571.

    CAS  PubMed  Google Scholar 

  110. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR . Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24: 431–436.

    CAS  PubMed  Google Scholar 

  111. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367: 825–831.

    CAS  PubMed  Google Scholar 

  112. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370: 1209–1218.

    CAS  PubMed  Google Scholar 

  113. Richardson PG, Mitsiades C, Hideshima T, Anderson KC . Lenalidomide in multiple myeloma. Expert Rev Anticancer Ther 2006; 6: 1165–1173.

    CAS  PubMed  Google Scholar 

  114. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100: 3063–3067.

    CAS  PubMed  Google Scholar 

  115. Schey SA, Fields P, Bartlett JB, Clarke IA, Ashan G, Knight RD et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004; 22: 3269–3276.

    CAS  PubMed  Google Scholar 

  116. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357: 2123–2132.

    CAS  PubMed  Google Scholar 

  117. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357: 2133–2142.

    CAS  PubMed  Google Scholar 

  118. Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Williams M et al. A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group. Blood 2007; 110 (11; abstract 74): 121.

    Google Scholar 

  119. Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore Sr DF, Whittenberger BF et al. Superiority of Lenalidomide (Len) Plus High-Dose Dexamethasone (HD) Compared to HD Alone as Treatment of Newly-Diagnosed Multiple Myeloma (NDMM): Results of the Randomized, Double-Blinded, Placebo-Controlled SWOG Trial S0232. Blood 2007; 110 (11; abstract 77): 121.

    Google Scholar 

  120. Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol 2007; 25: 4459–4465.

    CAS  PubMed  Google Scholar 

  121. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617.

    CAS  PubMed  Google Scholar 

  122. San Miguel JF, Schlag R, Khuageva N, Shpilberg O, Dimopoulos M, Kropff M et al. MY-3002: A Phase 3 Study Comparing BortezomibMelphalanPrednisone (VMP) with MelphalanPrednisone (MP) in Newly Diagnosed Multiple Myeloma. Blood 2007; 110 (11; abstract 73): 121.

    Google Scholar 

  123. Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH . Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 2003; 100: 9946–9951.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Richardson PG, Mitsiades C, Hideshima T, Anderson KC . Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med 2006; 57: 33–47.

    CAS  PubMed  Google Scholar 

  125. Podar K, Anderson KC . Caveolin-1 as a potential new therapeutic target in multiple myeloma. Cancer Lett 2006; 233: 10–15.

    CAS  PubMed  Google Scholar 

  126. Harousseau JL, Attal M, Coiteux V, Stoppa A, Hulin C, Benboubker L et al. Bortezomib (VELCADE®) Plus Dexamethasone as Induction Treatment Prior to Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: Preliminary Results of an IFM Phase II Study. J Clin Oncol 2005, ASCO Annual Meeting Proceedings. 2005;23(16S; Part I of II, (1 June Supplement)):2005: 6653.

  127. Macherla VR, Mitchell SS, Manam RR, Reed KA, Chao TH, Nicholson B et al. Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor. J Med Chem 2005; 48: 3684–3687.

    CAS  PubMed  Google Scholar 

  128. Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005; 8: 407–419.

    CAS  PubMed  Google Scholar 

  129. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007; 67: 6383–6391.

    CAS  PubMed  Google Scholar 

  130. Chauhan D, Singh A, Brahmandam M, Podar K, Hideshima T, Richardson P et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008; 111: 1654–1664.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mitsiades N, Mitsiades CS, Richardson PG, McMullan C, Poulaki V, Fanourakis G et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003; 101: 4055–4062.

    CAS  PubMed  Google Scholar 

  132. Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P 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: 3441–3449.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Badros A, Philip S, Niesvizky R, Goloubeva O, Harris C, Zweibel J et al. Phase I Trial of Suberoylanilide Hydroxamic Acid (SAHA) + Bortezomib (Bort) in Relapsed Multiple Myeloma (MM) Patients (pts). Blood 2007; 110 (11; abstract 1168): 354a.

    Google Scholar 

  134. Weber DM, Jagannath S, Mazumder A, Sobecks R, Schiller GJ, Gavino M et al. Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma. Blood 2007; 110: 355a, abstract 1172.

    Google Scholar 

  135. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93: 1658–1667.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  137. Vacca A, Ria R, Presta M, Ribatti D, Iurlaro M, Merchionne F et al. alpha(v)beta(3) integrin engagement modulates cell adhesion, proliferation, and protease secretion in human lymphoid tumor cells. Exp Hematol 2001; 29: 993–1003.

    CAS  PubMed  Google Scholar 

  138. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332: 83–85.

    CAS  PubMed  Google Scholar 

  139. Klein B, Zhang XG, Lu ZY, Bataille R . Interleukin-6 in human multiple myeloma. Blood 1995; 85: 863–872.

    CAS  PubMed  Google Scholar 

  140. Wen XY, Stewart AK, Sooknanan RR, Henderson G, Hawley TS, Reimold AM 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: 173–178.

    CAS  PubMed  Google Scholar 

  141. Chauhan D, Li G, Auclair D, Hideshima T, Richardson P, Podar K et al. Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays. Blood 2003; 101: 3606–3614.

    CAS  PubMed  Google Scholar 

  142. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 2001; 412: 300–307.

    CAS  PubMed  Google Scholar 

  143. 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: 321–329.

    CAS  PubMed  Google Scholar 

  144. Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 2007; 11: 349–360.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Ernst M, Gearing DP, Dunn AR . Functional and biochemical association of Hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells. Embo J 1994; 13: 1574–1584.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Schaeffer M, Schneiderbauer M, Weidler S, Tavares R, Warmuth M, de Vos G et al. Signaling through a novel domain of gp130 mediates cell proliferation and activation of Hck and Erk kinases. Mol Cell Biol 2001; 21: 8068–8081.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Podar K, Mostoslavsky G, Sattler M, Tai YT, Hayashi T, Catley LP et al. Critical role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6- induced proliferation and survival of MM cells. J Biol Chem 2004; 279: 21658–21665.

    CAS  PubMed  Google Scholar 

  148. Le Gouill S, Podar K, Harousseau JL, Anderson KC . Mcl-1 regulation and its role in multiple myeloma. Cell Cycle 2004; 3: 1259–1262.

    CAS  PubMed  Google Scholar 

  149. Chauhan D, Anderson KC . Mechanisms of cell death and survival in multiple myeloma (MM): therapeutic implications. Apoptosis 2003; 8: 337–343.

    CAS  PubMed  Google Scholar 

  150. Chauhan D, Neri P, Velankar M, Podar K, Hideshima T, Fulciniti M et al. Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood 2007; 109: 1220–1227.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Ferrara N, Hillan KJ, Gerber HP, Novotny W . Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3: 391–400.

    CAS  PubMed  Google Scholar 

  152. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: 427–434.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lin B, Podar K, Gupta D, Tai YT, Li S, Weller E 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: 5019–5026.

    CAS  PubMed  Google Scholar 

  154. Aggarwal R, Ghobrial IM, Roodman GD . Chemokines in multiple myeloma. Exp Hematol 2006; 34: 1289–1295.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 2007; 109: 2708–2717.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Menu E, Asosingh K, Indraccolo S, De Raeve H, Van Riet I, Van Valckenborgh E et al. The involvement of stromal derived factor 1alpha in homing and progression of multiple myeloma in the 5TMM model. Haematologica 2006; 91: 605–612.

    CAS  PubMed  Google Scholar 

  157. De Clercq E . The bicyclam AMD3100 story. Nat Rev Drug Discov 2003; 2: 581–587.

    CAS  PubMed  Google Scholar 

  158. Pelus LM . Peripheral blood stem cell mobilization: new regimens, new cells, where do we stand. Curr Opin Hematol 2008; 15: 285–292.

    PubMed  PubMed Central  Google Scholar 

  159. Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf D, Badel K et al. Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin′s lymphoma. J Clin Oncol 2004; 22: 1095–1102.

    CAS  PubMed  Google Scholar 

  160. DiPersio J, Stadtmauer EA, Nademanee AP, Stiff P, Micallef I, Angell J et al. In vivo mobilization of multiple myeloma cells out of the bone marrow using the CXCR4 inhibitor AMD3100 and bortezomib: implications for sensitization of myeloma cells to apoptosis. Blood 2007; 110: abstract #445.

  161. Podar K, Hideshima T, Tai YT, Richardson PG, Chauhan D, Anderson KC . Emerging therapies for multiple myeloma. Am J Cancer 2006; 5: 141–153.

    CAS  Google Scholar 

  162. Tai YT, Catley L, Li XF, Coffey R, Breitkreutz I, Bae J et al. Immunomodulatory drug Lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 2005; 65 (24) 11712–11720.

    CAS  PubMed  Google Scholar 

  163. 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: 4519–4527.

    CAS  PubMed  Google Scholar 

  164. Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004; 103: 689–694.

    CAS  PubMed  Google Scholar 

  165. Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004; 103: 3148–3157.

    CAS  PubMed  Google Scholar 

  166. Moreaux J, Hose D, Jourdan M, Reme T, Hundemer M, Moos 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: 803–811.

    CAS  PubMed  Google Scholar 

  167. Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 2005; 106: 1021–1030.

    CAS  PubMed  Google Scholar 

  168. Birmann BM, Giovannucci E, Rosner B, Anderson KC, Colditz GA . Body mass index, physical activity, and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev 2007; 16: 1474–1478.

    PubMed  Google Scholar 

  169. Abroun S, Ishikawa H, Tsuyama N, Liu S, Li FJ, Otsuyama K et al. Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I that highly express IL-6 receptor alpha myeloma cells. Blood 2004; 103: 2291–2298.

    CAS  PubMed  Google Scholar 

  170. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Akiyama M 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: 221–230.

    CAS  PubMed  Google Scholar 

  171. Podar K, Raab MS, Chauhan D, Anderson KC . The therapeutic role of targeting protein kinase C in solid and hematologic malignancies. Expert Opin Investig Drugs 2007; 16: 1693–1707.

    CAS  PubMed  Google Scholar 

  172. Sharkey J, Khong T, Spencer A . PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. Blood 2007; 109: 1712–1719.

    CAS  PubMed  Google Scholar 

  173. Podar K, Raab MS, Zhang J, McMillin D, Breitkreutz I, Tai YT 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: 1669–1677.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Moreau AS, Jia X, Ngo HT, Leleu X, O’Sullivan G, Alsayed Y et al. Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstrom macroglobulinemia. Blood 2007; 109: 4964–4972.

    CAS  PubMed  Google Scholar 

  175. Mitsiades CS, Hayden PJ, Anderson KC, Richardson PG . From the bench to the bedside: emerging new treatments in multiple myeloma. Best pract res 2007; 20: 797–816.

    CAS  Google Scholar 

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Acknowledgements

This work was supported by Multiple Myeloma Research Foundation (MMRF) Senior Research Grant Award and Dunkin’ Donuts Rising Star Award (KP), as well as National Institutes of Health Grants IP50 CA100707, PO-1 78378 and RO-1 CA 50947; The Myeloma Research Fund; and the LeBow Family Fund to Cure Myeloma (KCA)

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Podar, K., Chauhan, D. & Anderson, K. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 23, 10–24 (2009). https://doi.org/10.1038/leu.2008.259

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