Myc/Max Family of Transcription Factors and bcl-2 are Involved in Drug-induced Apoptosis of Myeloma Cells

  • D. S. Siegel
  • J. A. Terry
  • J. Koury
  • B. Barlogie
  • J. Epstein
  • R. Feinman
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 224)


Cell homeostasis is controlled by a balance between proliferation, growth arrest and apoptosis. It is becoming increasingly evident that dysregulation of genes that control apoptosis contributes to the pathogenesis of disease such as cancer and autoimmune disease (1). In multiple myeloma, myeloma cells are terminally differentiated and fail to apoptose. Glucocorticoids such as dexamethasone (Dex) are often used in the treatment of myeloma, either alone or in combination with cytotoxic agents (2, 3). Similarly, IL-6 in the bone marrow environment protects immature myeloma cells form Dex-induced apoptosis (4). However, with prolonged treatment, patients develop resistance to these agents. It is well established that both glucocorticoids and chemotherapeutic drugs are potent inducers of cell death, by apoptosis (1). In fact, recent studies have demonstrated that Dex-induced apoptosis in several human myeloma cell lines and that interleukin-6 (IL-6), a B cell differentiation/survival factor, protected them from Dex-induced apoptosis (5, 6, Epstein J personal communication). The molecular mechanisms that govern these processes are not fully understood. Restoration of the apoptopic response in myeloma cells could lead to the development of effective therapy for multiple myeloma.


Multiple Myeloma Myeloma Cell Myeloma Cell Line Upstream Stimulatory Factor Human Myeloma Cell Line 
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  1. 1.
    Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462PubMedCrossRefGoogle Scholar
  2. 2.
    Barlogie B, Epstein J (1990) Multiple myeloma:biology and therapy. J. Cancer Res. & Clin. Oncol. 116:109–111CrossRefGoogle Scholar
  3. 3.
    Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B (1992) Primary dexamethasonetreatment of multiple myeloma. Blood 80:887–890PubMedGoogle Scholar
  4. 4.
    Grigorieva I, Thomas X, Woodliff J, Epstein J (1995) The bone marrow environment contributes to dexamethasone resistance in multiple myeloma. Blood 86(Suppl 1): 728Google Scholar
  5. 5.
    Hardin J, Macleod S, Grigorieva I, Chang R, Barlogie B, Xiao H, Epstein J (1994) Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood 84:3063–3070PubMedGoogle Scholar
  6. 6.
    Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J (1995) Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell. Immunol. 162:248–255PubMedCrossRefGoogle Scholar
  7. 7.
    Helmberg A, Auphan N, Caelles C, Karin M (1995) Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. EMBO J. 14:452–460PubMedCentralPubMedGoogle Scholar
  8. 8.
    Blobel GA, Orkin SH (1996) Estrogen-induced apoptosis by inhibition of the erythroid transcription factor GATA-1. Mol. Cell Biol. 16:1687–1694PubMedCentralPubMedGoogle Scholar
  9. 9.
    Petersson M, Jernberg-Wiklund, Larssin LG, Sundstrom C, Givol I, Tsujimoto Y, Nilsson K (1992) Expression of the bcl-2 gene in human multiple myeloma cell lines and normal plasma cells. Blood 79:495–502Google Scholar
  10. 10.
    Skopelitou A, Hadiyannakis M, Tsenga A, Theocharis S, Alexopoulou V, Kittas C, Agnantis N (1993) Expression of c-myc p62 oncoprotein in multiple myeloma: An immunohistochemical study of 180 cases. Anticancer Res. 13:1091–1095PubMedGoogle Scholar
  11. 11.
    Selvanyagam P, Blick M, Narni F, van Tuinen P, Ledbetter DH, Alexanian R, Saunders F, Barlogie B (1988) Alteration and abnormal expression of the c-myc oncogene in human multiple myeloma. Blood 71:30–35Google Scholar
  12. 12.
    Zhang X, Siegel D, Pearse R, Michaeli J (1995) Distinct apoptotic pathways in human myeloma cells in response to dexamethasone and the differentiation inducer hexamethylene bisacetamide. Blood 86, Suppl 1:237Google Scholar
  13. 13.
    Thulasi R, Harbour DV, Thompson EB (1993) Suppression of c-myc is a critical step in glucocorticoid-induced human leukemic cell lysis. J.Biol.Chem. 268:18306–18312PubMedGoogle Scholar
  14. 14.
    Rhee K, Bresnaham W, Hirai A, Hirai M, Thompson EA (1995) c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation. Cancer Res. 55:4188–4195PubMedGoogle Scholar
  15. 15.
    Eliot HE, Borner MM, Sinha BK (1995) Differential oncogene expression and susceptibility to apoptosis in the human leukemia HL60 cell lines:implications for etoposide resistance. Anticancer Res. 15:729–734PubMedGoogle Scholar
  16. 16.
    Lee H, Arsura M, Wu M, Duyao M, Buckler AJ, Sonenshein GE (1995) Role of Rel-related factors in control of c-myc gene transcription in receptor-mediated apoptosis of the murine B cell WEHI 231 line. J. Exp. Med. 181:1169–1177PubMedCrossRefGoogle Scholar
  17. 17.
    Ryan KM, Birnie GD (1996) Myc oncogenes: the enigmatic family. Biochem. J. 14:713–721Google Scholar
  18. 18.
    Blackwood EM, Eisenman RN (1991) Max: A helix-loop-helix zipper protein that forms a sequence-specific DNA binding complex with myc. Science 251:1211–1217PubMedCrossRefGoogle Scholar
  19. 19.
    Hata H, Xiao H, Petrucci MT, Woodliff J, Chang R, Epstein J (1993) Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells. Blood 81:3357–3364PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • D. S. Siegel
    • 1
  • J. A. Terry
    • 1
  • J. Koury
    • 1
  • B. Barlogie
    • 1
  • J. Epstein
    • 1
  • R. Feinman
    • 1
  1. 1.Division of Hematology and OncologyUniversity of Arkansas for Medical SciencesLittle RockUSA

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