Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Growth factors and antiapoptotic signaling pathways in multiple myeloma

Leukemia volume 19, pages 2177–2185 (2005)Cite this article

Abstract

Failure of myeloma cells to undergo apoptosis plays an important role in the accumulation of myeloma cells within the bone marrow (BM). Moreover, inhibition of drug-induced apoptosis has been indicated as a major contributor of drug resistance in myeloma. The BM microenvironment promotes survival and blocks the apoptotic effects of various cytotoxic agents through the production of cytokines as well as through direct physical interactions. Several antiapoptotic proteins and antiapoptotic signaling cascades have been identified that contribute to the antiapoptotic phenotype of the myeloma cell. In this review, we discuss mechanisms that result in enhanced survival and drug resistance of myeloma cells. Insight into these mechanisms is essential to make progress in the therapy of myeloma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Johnstone RW, Ruefli AA, Lowe SW . Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108: 153–164.

    CAS  PubMed  Google Scholar 

  2. 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  PubMed Central  Google Scholar 

  3. Hazlehurst LA, Enkemann SA, Beam CA, Argilagos RF, Painter J, Shain KH et al. Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Res 2003; 63: 7900–7906.

    CAS  PubMed  Google Scholar 

  4. Chatterjee M, Honemann D, Lentzsch S, Bommert K, Sers C, Herrmann P et al. In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway. Blood 2002; 100: 3311–3318.

    CAS  PubMed  Google Scholar 

  5. Nefedova Y, Landowski TH, Dalton WS . Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 2003; 17: 1175–1182.

    CAS  PubMed  Google Scholar 

  6. Schmidmaier R, Baumann P, Simsek M, Dayyani F, Emmerich B, Meinhardt G . The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase. Blood 2004; 104: 1825–1832.

    CAS  PubMed  Google Scholar 

  7. Lokhorst HM, Lamme T, de Smet M, Klein S, de Weger RA, van Oers R et al. Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures. Blood 1994; 84: 2269–2277.

    CAS  PubMed  Google Scholar 

  8. 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 

  9. 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 

  10. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor–stromal cell interactions in multiple myeloma. Blood 2000; 95: 2630–2636.

    CAS  PubMed  Google Scholar 

  11. Bisping G, Leo R, Wenning D, Dankbar B, Padro T, Kropff M et al. Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood 2003; 101: 2775–2783.

    CAS  PubMed  Google Scholar 

  12. Frassanito MA, Cusmai A, Iodice G, Dammacco F . Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis. Blood 2001; 97: 483–489.

    CAS  PubMed  Google Scholar 

  13. Hardin J, MacLeod S, Grigorieva I, Chang R, Barlogie B, Xiao H et al. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood 1994; 84: 3063–3070.

    CAS  PubMed  Google Scholar 

  14. Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Henze C, Loffler D, Koczan D et al. Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood 2004; 103: 242–251.

    CAS  PubMed  Google Scholar 

  15. Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 1997; 159: 2212–2221.

    CAS  PubMed  Google Scholar 

  16. 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: 6763–6770.

    CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. Oshiro MM, Landowski TH, Catlett-Falcone R, Hazlehurst LA, Huang M, Jove R et al. Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells. Clin Cancer Res 2001; 7: 4262–4271.

    CAS  PubMed  Google Scholar 

  20. Ferlin M, Noraz N, Hertogh C, Brochier J, Taylor N, Klein B . Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. Br J Haematol 2000; 111: 626–634.

    CAS  PubMed  Google Scholar 

  21. 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 

  22. 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: 4138–4146.

    CAS  PubMed  Google Scholar 

  23. Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D 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: 5673–5683.

    CAS  PubMed  Google Scholar 

  24. Abboud SL, Bethel CR, Aron DC . Secretion of insulinlike growth factor I and insulinlike growth factor-binding proteins by murine bone marrow stromal cells. J Clin Invest 1991; 88: 470–475.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Kimlinger TK et al. Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression. Blood 2004; 104: 1159–1165.

    CAS  PubMed  Google Scholar 

  26. 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  Google Scholar 

  27. Lentzsch S, Chatterjee M, Gries M, Bommert K, Gollasch H, Dorken B et al. PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia 2004; 18: 1883–1890.

    CAS  PubMed  Google Scholar 

  28. Le Gouill S, Podar K, Amiot M, Hideshima T, Chauhan D, Ishitsuka K et al. VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood 2004; 104: 2886–2892.

    CAS  PubMed  Google Scholar 

  29. 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 

  30. Podar K, Catley LP, Tai YT, Shringarpure R, Carvalho P, Hayashi T et al. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. Blood 2004; 103: 3474–3479.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Mori Y, Shimizu N, Dallas M, Niewolna M, Story B, Williams PJ et al. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 2004; 104: 2149–2154.

    CAS  PubMed  Google Scholar 

  33. 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 

  34. Rowley M, Van Ness B . Activation of N-ras and K-ras induced by interleukin-6 in a myeloma cell line: implications for disease progression and therapeutic response. Oncogene 2002; 21: 8769–8775.

    CAS  PubMed  Google Scholar 

  35. 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: 3126–3135.

    CAS  PubMed  Google Scholar 

  36. Liu P, Leong T, Quam L, Billadeau D, Kay NE, Greipp P et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 1996; 88: 2699–2706.

    CAS  PubMed  Google Scholar 

  37. Neri A, Murphy JP, Cro L, Ferrero D, Tarella C, Baldini L et al. Ras oncogene mutation in multiple myeloma. J Exp Med 1989; 170: 1715–1725.

    CAS  PubMed  Google Scholar 

  38. Corradini P, Ladetto M, Voena C, Palumbo A, Inghirami G, Knowles DM et al. Mutational activation of N- and K-ras oncogenes in plasma cell dyscrasias. Blood 1993; 81: 2708–2713.

    CAS  PubMed  Google Scholar 

  39. Billadeau D, Liu P, Jelinek D, Shah N, LeBien TW, Van Ness B . Activating mutations in the N- and K-ras oncogenes differentially affect the growth properties of the IL-6-dependent myeloma cell line ANBL6. Cancer Res 1997; 57: 2268–2275.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS . Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 1999; 93: 3044–3052.

    CAS  PubMed  Google Scholar 

  42. Bharti AC, Donato N, Singh S, Aggarwal BB . Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 2003; 101: 1053–1062.

    CAS  PubMed  Google Scholar 

  43. 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 

  44. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99: 4525–4530.

    CAS  PubMed  Google Scholar 

  45. 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 

  46. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 2002; 99: 4079–4086.

    CAS  PubMed  Google Scholar 

  47. 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 

  48. 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 

  49. Hsu J, Shi Y, Krajewski S, Renner S, Fisher M, Reed JC et al. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001; 98: 2853–2855.

    CAS  PubMed  Google Scholar 

  50. Hyun T, Yam A, Pece S, Xie X, Zhang J, Miki T et al. Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood 2000; 96: 3560–3568.

    CAS  PubMed  Google Scholar 

  51. Shi Y, Hsu JH, Hu L, Gera J, Lichtenstein A . Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. J Biol Chem 2002; 277: 15712–15720.

    CAS  PubMed  Google Scholar 

  52. Stromberg T, Dimberg A, Hammarberg A, Carlson K, Osterborg A, Nilsson K et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 2004; 103: 3138–3147.

    PubMed  Google Scholar 

  53. Puthier D, Bataille R, Amiot M . IL-6 up-regulates mcl-1 in human myeloma cells through JAK/STAT rather than ras/MAP kinase pathway. Eur J Immunol 1999; 29: 3945–3950.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL . SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 2004; 103: 4630–4635.

    CAS  PubMed  Google Scholar 

  56. 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 

  57. Gross A, McDonnell JM, Korsmeyer SJ . BCL-2 family members and the mitochondria in apoptosis. Genes Dev 1999; 13: 1899–1911.

    CAS  PubMed  Google Scholar 

  58. Sangfelt O, Osterborg A, Grander D, Anderbring E, Ost A, Mellstedt H et al. Response to interferon therapy in patients with multiple myeloma correlates with expression of the Bcl-2 oncoprotein. Int J Cancer 1995; 63: 190–192.

    CAS  PubMed  Google Scholar 

  59. Ong F, van Nieuwkoop JA, Groot-Swings GM, Hermans J, Harvey MS, Kluin PM et al. Bcl-2 protein expression is not related to short survival in multiple myeloma. Leukemia 1995; 9: 1282–1284.

    CAS  PubMed  Google Scholar 

  60. Renner S, Weisz J, Krajewski S, Krajewska M, Reed JC, Lichtenstein A . Expression of BAX in plasma cell dyscrasias. Clin Cancer Res 2000; 6: 2371–2380.

    CAS  PubMed  Google Scholar 

  61. Iyer R, Ding L, Batchu RB, Naugler S, Shammas MA, Munshi NC . Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone resistance in multiple myeloma. Leuk Res 2003; 27: 73–78.

    CAS  PubMed  Google Scholar 

  62. Strasser A, Whittingham S, Vaux DL, Bath ML, Adams JM, Cory S et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci USA 1991; 88: 8661–8665.

    CAS  PubMed  Google Scholar 

  63. Strasser A, Harris AW, Cory S . E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene 1993; 8: 1–9.

    CAS  PubMed  Google Scholar 

  64. Bissonnette RP, Echeverri F, Mahboubi A, Green DR . Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 1992; 359: 552–554.

    CAS  PubMed  Google Scholar 

  65. Tu Y, Xu FH, Liu J, Vescio R, Berenson J, Fady C et al. Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. Blood 1996; 88: 1805–1812.

    CAS  PubMed  Google Scholar 

  66. Panaretakis T, Pokrovskaja K, Shoshan MC, Grander D . Activation of Bak, Bax, and BH3-only proteins in the apoptotic response to doxorubicin. J Biol Chem 2002; 277: 44317–44326.

    CAS  PubMed  Google Scholar 

  67. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 2002; 99: 14374–14379.

    CAS  PubMed  Google Scholar 

  68. Schwarze MM, Hawley RG . Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res 1995; 55: 2262–2265.

    CAS  PubMed  Google Scholar 

  69. van de Donk NW, Kamphuis MM, Van Dijk M, Borst HP, Bloem AC, Lokhorst HM . Chemosensitization of myeloma plasma cells by an antisense-mediated downregulation of Bcl-2 protein. Leukemia 2003; 17: 211–219.

    CAS  PubMed  Google Scholar 

  70. Derenne S, Monia B, Dean NM, Taylor JK, Rapp MJ, Harousseau JL 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: 194–199.

    CAS  PubMed  Google Scholar 

  71. Pei XY, Dai Y, Grant S . The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 2003; 17: 2036–2045.

    CAS  PubMed  Google Scholar 

  72. van de Donk NW, De Weerdt O, Veth G, Eurelings M, van Stralen E, Frankel SR et al. G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 2004; 18: 1078–1084.

    CAS  PubMed  Google Scholar 

  73. Badros AZ, Goloubeva O, Rapoport AP, Ratterree B, Gahres N, Meisenberg B et al. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol 2005; 23: 4089–4099.

    CAS  PubMed  Google Scholar 

  74. Chanan-Khan A, Niesvisky R, Hohl R, Zimmerman T, Christiansen N, Schiller G et al. Randomized multicenter phase 3 trial of high-dose dexamethasone (dex) with or without oblimersen sodium (G3139; Bcl-2 antisense; Genasense) for patients with advanced multiple myeloma (MM). Blood 2004; 104: 1477a.

    Google Scholar 

  75. Park WH, Seol JG, Kim ES, Hyun JM, Jung CW, Lee CC et al. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res 2000; 60: 3065–3071.

    CAS  PubMed  Google Scholar 

  76. Puthier D, Derenne S, Barille S, Moreau P, Harousseau JL, Bataille R et al. Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J Haematol 1999; 107: 392–395.

    CAS  PubMed  Google Scholar 

  77. Pollett JB, Trudel S, Stern D, Li ZH, Stewart AK . Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance. Blood 2002; 100: 3819–3821.

    CAS  PubMed  Google Scholar 

  78. Cheung WC, Kim JS, Linden M, Peng L, Van Ness B, Polakiewicz RD et al. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. J Clin Invest 2004; 113: 1763–1773.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Tu Y, Renner S, Xu F, Fleishman A, Taylor J, Weisz J et al. BCL-X expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 1998; 58: 256–262.

    CAS  PubMed  Google Scholar 

  80. Craig RW . MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis. Leukemia 2002; 16: 444–454.

    CAS  PubMed  Google Scholar 

  81. Spets H, Stromberg T, Georgii-Hemming P, Siljason J, Nilsson K, Jernberg-Wiklund H . Expression of the bcl-2 family of pro- and anti-apoptotic genes in multiple myeloma and normal plasma cells: regulation during interleukin-6(IL-6)-induced growth and survival. Eur J Haematol 2002; 69: 76–89.

    CAS  PubMed  Google Scholar 

  82. Munshi NC, Hideshima T, Carrasco D, Shammas M, Auclair D, Davies F et al. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood 2004; 103: 1799–1806.

    CAS  PubMed  Google Scholar 

  83. Wuilleme-Toumi S, Robillard N, Gomez P, Moreau P, Le Gouill S, Avet-Loiseau H et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia 2005; 19: 1248–1252.

    CAS  PubMed  Google Scholar 

  84. Jourdan M, Veyrune JL, Vos JD, Redal N, Couderc G, Klein B . A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells. Oncogene 2003; 22: 2950–2959.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang B, Potyagaylo V, Fenton RG . IL-6-independent expression of Mcl-1 in human multiple myeloma. Oncogene 2003; 22: 1848–1859.

    CAS  PubMed  Google Scholar 

  86. Dai Y, Pei XY, Rahmani M, Conrad DH, Dent P, Grant S . Interruption of the NF-kappaB pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. Blood 2004; 103: 2761–2770.

    CAS  PubMed  Google Scholar 

  87. 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 

  88. Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 2005; 106: 1042–1047.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. van de Donk NW, Kamphuis MM, Van Kessel B, Lokhorst HM, Bloem AC . Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. Blood 2003; 102: 3354–3362.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  91. Filippovich IV, Sorokina NI, Lisbona A, Cherel M, Chatal JF . Radiation-induced apoptosis in human myeloma cell line increases BCL-2/BAX dimer formation and does not result in BAX/BAX homodimerization. Int J Cancer 2001; 92: 651–660.

    CAS  PubMed  Google Scholar 

  92. 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 

  93. Chen Q, Gong B, Mahmoud-Ahmed AS, Zhou A, Hsi ED, Hussein M et al. Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma. Blood 2001; 98: 2183–2192.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Akay C, Thomas III C, Gazitt Y . Arsenic trioxide and paclitaxel induce apoptosis by different mechanisms. Cell Cycle 2004; 3: 324–334.

    CAS  PubMed  Google Scholar 

  95. Yasui H, Hideshima T, Hamasaki M, Roccaro AM, Shiraishi N, Kumar S et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood 2005; 106: 706–712.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Goldstein JL, Brown MS . Regulation of the mevalonate pathway. Nature 1990; 343: 425–430.

    CAS  PubMed  Google Scholar 

  97. van de Donk NW, Kamphuis MM, Lokhorst HM, Bloem AC . The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia 2002; 16: 1362–1371.

    CAS  PubMed  Google Scholar 

  98. van de Donk NW, Lokhorst HM, Nijhuis EH, Kamphuis MM, Bloem AC . Geranylgeranylated proteins are involved in the regulation of myeloma cell growth. Clin Cancer Res 2005; 11 (Part 1): 429–439.

    CAS  PubMed  Google Scholar 

  99. Shipman CM, Croucher PI, Russell RG, Helfrich MH, Rogers MJ . The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res 1998; 58: 5294–5297.

    CAS  PubMed  Google Scholar 

  100. Gordon S, Helfrich MH, Sati HI, Greaves M, Ralston SH, Culligan DJ et al. Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma. Br J Haematol 2002; 119: 475–483.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was financially supported by a grant from the Dutch Cancer Society (KWF) and a grant from the International Myeloma Foundation (IMF).

Author information

Authors and Affiliations

  1. Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    N W C J van de Donk & A C Bloem

  2. Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    H M Lokhorst

Authors
  1. N W C J van de Donk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H M Lokhorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A C Bloem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A C Bloem.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van de Donk, N., Lokhorst, H. & Bloem, A. Growth factors and antiapoptotic signaling pathways in multiple myeloma. Leukemia 19, 2177–2185 (2005). https://doi.org/10.1038/sj.leu.2403970

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403970

Keywords

This article is cited by

Search

Advanced search

Quick links