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.

  • Original Article
  • Published:

Lymphoma

Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-Hodgkin's lymphoma cells

Leukemia volume 21, pages 1521–1531 (2007)Cite this article

Abstract

Stromal cells are an essential component of the bone marrow microenvironment that regulate or supports tumor survival. In this study we therefore studied the role of stromal cells in lymphoma cell survival. We demonstrated that adhesion of the B-cell lymphoma cell lines SUDH-4 and 10 to bone marrow stroma inhibited mitoxantrone-induced apoptosis. This adhesion-dependent inhibition of mitoxantrone-induced apoptosis correlated with decreased activation of caspases-8 and 9, and cleavage of caspase 3 and PARP. Electrophoretic mobility shift assays (EMSA) analysis demonstrated significantly increased NF-κB binding activity in lymphoma cells adhered to stroma cells compared to lymphoma cells in suspension. This DNA binding activity could be attributed to cell adhesion-mediated proteolysis of the NF-κB precursor, p100 (NF-κB2). This resulted in the generation of active p52, which translocated to the nucleus in complex with p65 and RelB. Coculture with stromal cells also induced expression of the NF-κB-regulated anti-apoptotic molecules, XIAP, cIAP1 and cIAP2. Inhibition of NF-κB significantly suppressed HS-5-induced protection against apoptosis in lymphoma cell lines as well as in primary lymphoma cells. Thus, bone marrow stroma protects B-cell lymphoma cells against apoptosis, at least in part through activation of NF-κB dependent mechanism involving up-regulation of NF-κB regulated antiapoptotic proteins. Consequently, this study suggests a new approach to decrease the resistance of lymphoma to chemotherapy.

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
Figure 5

Similar content being viewed by others

References

  1. Staudt LM, Wilson WH . Focus on lymphomas. Cancer Cell 2002; 2: 363–366.

    Article  CAS  PubMed  Google Scholar 

  2. Flinn IW . Lymphoma therapy: the challenges ahead. Curr Opin Oncol 2002; 14: 473–474.

    Article  PubMed  Google Scholar 

  3. DeClerck YA, Mercurio AM, Stack MS, Chapman HA, Zutter MM, Muschel RJ et al. Proteases, extracellular matrix, and cancer. Am J Pathol 2004; 164: 1131–1139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hall BM, Gibson LF . Regulation of lymphoid and myeloid leukemic cell survival: role of stromal cell adhesion molecules. Leuk Lymphoma 2004; 45: 35–48.

    Article  CAS  PubMed  Google Scholar 

  5. Li G, Satyamoorthy K, Meier F, Berking C, Bogenrieder T, Herlyn M . Function and regulation of melanoma-stromal fibroblast interactions: when seeds meet soil. Oncogene 2003; 22: 3162–3171.

    Article  CAS  PubMed  Google Scholar 

  6. Bertrand FE, Eckfeldt CE, Fink JR, Lysholm AS, Pribyl JA, Shah N et al. Microenvironmental influences on human B-cell development. Immunol Rev 2000; 175: 175–186.

    Article  CAS  PubMed  Google Scholar 

  7. Conlan MG, Bast M, Armitage JO, Weisenburger DD . Bone marrow involvement by non-Hodgkin's lymphoma: the clinical significance of morphologic discordance between the lymph node and bone marrow. Nebraska Lymphoma Study Group. J Clin Oncol 1990; 8: 1163–1172.

    Article  CAS  PubMed  Google Scholar 

  8. Viswanatha D, Foucar K . Hodgkin and non-Hodgkin lymphoma involving bone marrow. Semin Diagn Pathol 2003; 20: 196–210.

    Article  PubMed  Google Scholar 

  9. Sharp JG, Joshi SS, Armitage JO, Bierman P, Coccia PF, Harrington DS et al. Significance of detection of occult non-Hodgkin's lymphoma in histologically uninvolved bone marrow by a culture technique. Blood 1992; 79: 1074–1080.

    CAS  PubMed  Google Scholar 

  10. Campana D, Coustan-Smith E, Manabe A, Kumagai M, Murti KG, Silvennoinen O et al. Human B-cell progenitors and bone marrow microenvironment. Hum Cell 1996; 9: 317–322.

    CAS  PubMed  Google Scholar 

  11. Gibson LF . Survival of B lineage leukemic cells: signals from the bone marrow microenvironment. Leuk Lymphoma 2002; 43: 19–27.

    Article  CAS  PubMed  Google Scholar 

  12. Coustan-Smith E, Gajjar A, Hijiya N, Razzouk BI, Ribeiro RC, Rivera GK et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 2004; 18: 499–504.

    Article  CAS  PubMed  Google Scholar 

  13. Bendall LJ, Daniel A, Kortlepel K, Gottlieb DJ . Bone marrow adherent layers inhibit apoptosis of acute myeloid leukemia cells. Exp Hematol 1994; 2213: 1252–1260.

    Google Scholar 

  14. Fortney JE, Zhao W, Wenger SL, Gibson LF . Bone marrow stromal cells regulate caspase 3 activity in leukemic cells during chemotherapy. Leuk Res 2001; 25: 901–907.

    Article  CAS  PubMed  Google Scholar 

  15. Panayiotidis P, Jones D, Ganeshaguru K, Foroni L, Hoffbrand AV . Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. Br J Haematol 1996; 92: 97–103.

    Article  CAS  PubMed  Google Scholar 

  16. Garrido SM, Appelbaum FR, Willman CL, Banker DE . Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Exp Hematol 2001; 29: 448–457.

    Article  CAS  PubMed  Google Scholar 

  17. Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M . Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia 2002; 16: 1713–1724.

    Article  CAS  PubMed  Google Scholar 

  18. Shain KH, Landowski TH, Dalton WS . Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. J Immunol 2002; 168: 2544–2553.

    Article  CAS  PubMed  Google Scholar 

  19. Dalton WS . Drug resistance and drug development in multiple myeloma. Semin Oncol 2002; 29: 21–25.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Damiano JS, Dalton WS . Integrin-mediated drug resistance in multiple myeloma. Leuk Lymphoma 2000; 38: 71–81.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M et al. Retroviral oncoprotein Tax induces processing of NF-κB2/p100 in T cells: evidence for the involvement of IKKα. EMBO J 2001; 20: 6805–6815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001; 293: 1495–1499.

    Article  CAS  PubMed  Google Scholar 

  28. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 1996; 274: 787–789.

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Bian X, McAllister-Lucas LM, Shao F, Schumacher KR, Feng Z, Porter AG et al. NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. J Biol Chem 2001; 276: 48921–48929.

    Article  CAS  PubMed  Google Scholar 

  31. Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C . The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNF alpha-induced apoptosis. Genes Dev 1999; 13: 382–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang CY, Mayo MW, Baldwin Jr AS . TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 1996; 274: 784–787.

    Article  CAS  PubMed  Google Scholar 

  33. Grumont RJ, Rourke IJ, Gerondakis S . Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev 1999; 13: 400–411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J . NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol 2001; 21: 5299–52305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen C, Edelstein LC, Gelinas C . The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x (L). Mol Cell Biol 2000; 20: 2687–2695.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW . Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci USA 1997; 94: 10057–10062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin Jr AS . NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998; 281: 1680–1683.

    Article  CAS  PubMed  Google Scholar 

  38. Mudry RE, Fortney JE, York T, Hall BM, Gibson LF . Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood 2000; 96: 1926–1932.

    CAS  PubMed  Google Scholar 

  39. Caligaris-Cappio F . Biology of chronic lymphocytic leukemia. Rev Clin Exp Hematol 2000; 4: 5–21.

    Article  CAS  PubMed  Google Scholar 

  40. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P . Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 1998; 91: 2387–2396.

    CAS  PubMed  Google Scholar 

  41. Manabe A, Murti KG, Coustan-Smith E, Kumaga M, Behm FG, Raimond SC et al. Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells. Blood 1994; 83: 758–766.

    CAS  PubMed  Google Scholar 

  42. Bradstock K, Bianchi A, Makrynikola V, Filshie R, Gottlieb D . Long-term survival and proliferation of precursor-B acute lymphoblastic leukemia cells on human bone marrow stroma. Leukemia 1996; 10: 813–820.

    CAS  PubMed  Google Scholar 

  43. Ricciardi MR, Petrucci MT, Gregori C, Ariola C, Lemoli RM, Fogli N et al. Reduced susceptibility to apoptosis correlates with kinetic quiescence in disease progression of chronic lymphocytic leukaemia. Br J Haematol 2001; 113: 391–399.

    Article  CAS  PubMed  Google Scholar 

  44. Cory S, Adams JM . The Bcl2 family: regulators of the cellular life-or-death switch. Nature Reviews Cancer 2002; 2: 647–656.

    Article  CAS  PubMed  Google Scholar 

  45. Wang X . The expanding role of mitochondria in apoptosis. Genes and Development 2001; 15: 2922–2933.

    CAS  PubMed  Google Scholar 

  46. Du C, Fang M, Li Y, Li L, Wang X . Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33–42.

    Article  CAS  PubMed  Google Scholar 

  47. Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102: 43–53.

    Article  CAS  PubMed  Google Scholar 

  48. Liston P, Fong WG, Korneluk RG . The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene 2003; 22: 8568–8580.

    Article  CAS  PubMed  Google Scholar 

  49. de Graaf AO, de Witte T, Jansen JH . Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer? Leukemia 2004; 18: 1751–1759.

    Article  CAS  PubMed  Google Scholar 

  50. de Graaf AO, Han van Krieken J, Tönnissen E, Wissink W, Locht L, Overes I et al. Expression of C-IAP1, C-IAP2 and SURVIVIN discriminates different types of lymphoid malignancies. Br J Haematol 2005; 130: 852–859.

    Article  CAS  PubMed  Google Scholar 

  51. Munzert G, Kirchner D, Stobbe H, Bergmann L, Schmid RM, Dohner H et al. Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosis. Blood 2002; 100: 3749–3756.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants American Cancer Society IRG 032 ACS (J Tao), National Cancer Institute Aging and Cancer Pilot Research Grant (to J Tao) and NIH P01 grant CA76292 (WS Dalton).

Author information

Authors and Affiliations

  1. Department of Interdisciplinary Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA

    T Lwin, L A Hazlehurst, Z Li, S Dessureault, E Sotomayor, L C Moscinski, W S Dalton & J Tao

Authors
  1. T Lwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L A Hazlehurst
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Dessureault
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Sotomayor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L C Moscinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W S Dalton
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Tao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lwin, T., Hazlehurst, L., Li, Z. et al. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-Hodgkin's lymphoma cells. Leukemia 21, 1521–1531 (2007). https://doi.org/10.1038/sj.leu.2404723

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404723

Keywords

This article is cited by

Search

Advanced search

Quick links