Skip to main content
SpringerLink
Log in

BCL-2 Expression in Childhood Leukemia Versus Spontaneous Apoptosis, Drug Induced Apoptosis, and in vitro Drug Resistance

  • Chapter
Drug Resistance in Leukemia and Lymphoma III

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 457))

Abstract

The antileukemic activity of cytotoxic drugs is increasingly thought to be the result of induction of apoptosis. Several proto-oncogenes have been related to the regulation of this process. In this study we evaluated the relation between bcl-2 expression, spontaneous and dexamethasone (DXM) induced apoptosis, and in vitro resistance to DXM, prednisolone (PRD) and cytarabine (ARA) determined using the total cell kill colorimetric methyl-thiazol-tetrazolium salt (MTT) assay, in childhood acute lymphoblastic leukemia (ALL). Drug resistance was expressed as the LC50 value, the drug concentration lethal to 50% of the cells. Fourty-six samples taken at initial diagnosis (iALL) and 31 samples taken at relapse (rALL) were incubated in culture medium, with and without DXM. Bcl-2 expression and apoptosis were measured flowcytometrically, the latter using DNA histogram analysis. Bcl-2 expression was 1.4 fold higher in rALL than in iALL (p=0.008). Both spontaneous and DXM induced apoptosis increased significantly from 0 to 48 hours (in up to 71%, 81% of the cells respectively). Bcl-2 expression was inversely correlated with the extent of spontaneous apoptosis after 24 hours in iALL (r=-0.40, p=0.05). Relapsed samples, but not samples obtained at presentation, expressing high levels of bcl-2 displayed increased resistance to drug induced apoptosis (r=-0.63, p= 0.02). In iALL high bcl-2 expression appeared to be related to low LC50 values of ARA. No correlations were found for DXM or PRD. In conclusion, DXM excerts its cytotoxic effect at least partly by means of induction of apoptosis. Bcl-2 inhibits drug induced apoptosis in rALL. However in iALL bcl-2 expression is not associated with increased in vitro drug resistance, nor with increased resistance to drug induced apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Yunis JJ, Oken MM, Kaplan ME, Ensrud KM, Howe RR, Theologides A. Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin’s lymphoma. New England Journal of Medicine 1982, 307:1231–1236

    Article  PubMed  CAS  Google Scholar 

  2. Tsujimoto Y. Overexpression of the human bcl-2 gene product results in growth enhancement of Ebstein-Barr virus immortalized B cells. Proc Nat Acad Sci USA 1984, 86:1958–1962

    Article  Google Scholar 

  3. Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNA for Bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 1986, 47:19–28

    Article  PubMed  CAS  Google Scholar 

  4. Chen-Levy Z, Nourse J, Cleary ML. The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14:18) translocation. Mol Cell Biol 1989, 9:701–710

    PubMed  CAS  Google Scholar 

  5. Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer S. Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Ac Sci USA 1991, 16:8479–8483

    Google Scholar 

  6. Lu QL, Elia G, Lucas S, Thomas JA. Bcl-2 proto-oncogene expression in Ebstein-Barr virus associated nasopharyngeal carcinoma. Cancer 1993, 53:29–35

    CAS  Google Scholar 

  7. Nunez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ. Deregulated Bcl-2 gene-expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immumol 1991, 144:3602–3610

    Google Scholar 

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

    Article  Google Scholar 

  9. Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 1992, 359:554–556

    Article  PubMed  CAS  Google Scholar 

  10. Hickman JA. Apoptosis induced by anti-cancer drugs. Cancer Metast Rev 1992, 11:121–139

    Article  CAS  Google Scholar 

  11. Dive C, Hickman JA. Drug-target interactions: Only first step in the commitment to programmed cell death?. Br J Cancer 1991, 64:192–196

    Article  PubMed  CAS  Google Scholar 

  12. O’Connor PM, Wassermann K, Sarang M, Magrath I, Bohr VA, Kohn KW. Relation between DNA crosslinks, cell-cycle, and apoptosis in Burkitt’s lymphoma cell lines differing in sensitivity to nitrogen mustard. Cancer Res 1991, 51:6550–6557

    PubMed  Google Scholar 

  13. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anti-cancer agents. Cell 1993, 74:957–967

    Article  PubMed  CAS  Google Scholar 

  14. Miyashita T, Reed JC. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood 1990, 81:151–157

    Google Scholar 

  15. Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ. Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 1991, 67:879–888

    Article  PubMed  CAS  Google Scholar 

  16. Smets LA, Van Den Berg J, Acton D, Top B, Van Rooij H, Verweij-Janssen. Bcl-2 expression and mitochondrial activity in leukemic cells with different sensitivity to glucocorticoid-induced apoptosis. Blood 1994, 84:1613–1619

    PubMed  CAS  Google Scholar 

  17. Campos L, Rouault JP, Sabido O, Oriol P, Roubi N, Vasselon C, Archimbaud E, Magaud JP, Guyotot D. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor respons to chemotherapy. Blood 1993, 81:3091–3096

    PubMed  CAS  Google Scholar 

  18. Porwit-MacDonald A, Ivory K, Wilkinson S, Wheatley K, Wong L, Janossy G. Bcl-2 protein expression in normal human bone marrow precursors and in acute myelogenous leukemia. Leukemia 1995, 9:1191–1198

    PubMed  CAS  Google Scholar 

  19. Reed JC. Bcl2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 1995, 9:451–473

    PubMed  CAS  Google Scholar 

  20. Lotem J, Sachs L. Control of sensitivity to induction of apoptosis in myeloid leukemic cells by differentation and bcl-2 dependent and independent pathways. Cell Growth Differ 1994, 5:321–327

    PubMed  CAS  Google Scholar 

  21. Gala JL, Vermeylen C, Cornu G, Ferrant A, Michaux JL, Philippe M, Martiat P. High expression of bcl-2 is the rule in acute lymphoblastic leukemia, except in Burkitt subtype at presentation, and is not correlated with the prognosis. Ann Hematol 1994, 69:17–24

    Article  PubMed  CAS  Google Scholar 

  22. Maung ZT, Maclean ER, Reid MM, Pearson AD, Proctor SJ, Hamilton PJ, Hall AG. The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia. Br J Haematol 1994, 88:105–109

    Article  PubMed  CAS  Google Scholar 

  23. Coustan-Smith E, Kitanaka A, Pui CH, McNinch L, Evans WE, Raimondi SC, Behm FG, Arico M, Campana D. Clinical relevance of bcl-2 over-expression in childhood acute lymphoblastic leukemia. Blood 1996, 87:1140–1146

    PubMed  CAS  Google Scholar 

  24. Kaspers GJL, Veerman AJP, Pieters R, Broekema GJ, Huismans DR, Kazemier KM, Loonen AH, Rottier MMA, Van Zantwijk CH, Hahlen K, Van Wering ER. Mononuclear cells contaminating leukemic samples tested for cellular drug resistance using the methyl-thiazol-tetrazolium assay. Br J Cancer 1994, 10:1047–1052

    Article  Google Scholar 

  25. Castle VP, Heidelberger KP, Bromberg J, Ou X, Dole M, Nunez G. Expression of the apoptosis-surpressing gen bcl-2 in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Path 1993, 143:1543–1550

    PubMed  CAS  Google Scholar 

  26. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Ching LWK, Hsieh JT, Tu SM, Campbell ML. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992, 52:6940–6944

    PubMed  CAS  Google Scholar 

  27. Reed JC, Kitada S, Takayama S, Miyashita T. Regulation of chemoresistance by the bcl-2 oncoprotein in non-Hodgkin’s lymphoma and lymphoblastic leukemia cell lines. Ann Oncol 1994, 5:61–65

    Article  PubMed  Google Scholar 

  28. Klumper E, Pieters R, Veerman AJP, Huismans DR, Loonen AH, Hählen K, Kaspers GJL, Van Wering ER, Hartmann R, Henze G. In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. Blood 1995, 86:3681–3688

    Google Scholar 

  29. Salomons GS, Brady HJM, Verwijs-Janssen M, Van Den Berg JD, Hart AAM, Van Den Berg H, Behrendt H, Hählen K, Smets L. The Baxα: bcl-2 ratio modulates the respons to dexamethasone in leukemic cells and is highly variable in childhood acute leukemia. Fnt J Cancer 1997, 71:959–965

    Article  CAS  Google Scholar 

  30. Findley HW, Gu I, Yeager AM, Zhou M. Expression and regulation of bcl-2, bcl-xl and bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia. Blood 1997, 89:2986–2993

    PubMed  CAS  Google Scholar 

  31. Kaspers GJL, Pieters R, Klumper E, De Waal FC, Veerman AJP. Glucocorticoid resistance in childhood leukemia. Leuk & Lymphoma 1994, 13:187–201

    Article  CAS  Google Scholar 

  32. Schena M, Larsson LG, Gottardi D, Gaidano G, Carlsson M, Nilsson K, Caligaris-Cappio F. Growth and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells. Blood 1992, 11:2981–2989

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    E. G. Haarman, G. J. L. Kaspers, R. Pieters, C. H. van Zantwijk, G. J. Broekema & A. J. P. Veerman

  2. Department of Pediatric Hematology/Oncology, Sophia Children Hospital, 60 Dr. Molewaterplein, 3015 GJ, Rotterdam, The Netherlands

    K. Hählen

Authors
  1. E. G. Haarman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. J. L. Kaspers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Pieters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. H. van Zantwijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. J. Broekema
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Hählen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. J. P. Veerman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University Hospital Vrije Universiteit, Amsterdam, The Netherlands

    G. J. L. Kaspers , R. Pieters  & A. J. P. Veerman ,  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media New York

About this chapter

Cite this chapter

Haarman, E.G. et al. (1999). BCL-2 Expression in Childhood Leukemia Versus Spontaneous Apoptosis, Drug Induced Apoptosis, and in vitro Drug Resistance. In: Kaspers, G.J.L., Pieters, R., Veerman, A.J.P. (eds) Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol 457. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4811-9_35

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4811-9_35

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7180-9

  • Online ISBN: 978-1-4615-4811-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation