Skip to main content

Advertisement

SpringerLink
Log in

Bcl-2 and apoptosis in chronic lymphocytic leukemia

  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The Bcl-2 family of pro- and antiapoptotic proteins are key regulators of the apoptosis cascade and the mitochondrial-mediated pathway of caspase activation. Of this family, Bcl-2 was the first identified and remains the best characterized. Aberrant expression of Bcl-2 is common in chronic lymphocytic leukemia (CLL) and is associated with poor response to chemotherapy and decreased overall survival. Bcl-2 is an attractive target for novel therapeutic agents. Antisense oligonucleotides directed against Bcl-2 are effective in vitro and are being evaluated in clinical trials in CLL. Small molecule Bcl-2 inhibitors are in preclinical development and should be ready for clinical evaluation in the next few years. Strategies that induce apoptosis and bypass Bcl-2 may also be therapeutically useful in CLL. Thus, over the next decade, one can envision incorporating measurements of apoptotic proteins such as Bcl-2 into the risk assessment and treatment algorithms for individual patients. In addition, we anticipate that in the next decade, rationally designed therapies targeting specific molecular defects in the malignant CLL lymphocytes will be introduced into the clinic.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Schimmer A, Hedley DW, Penn LZ, et al.: Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view. Blood 2001, 98:3541–3553.

    Article  PubMed  CAS  Google Scholar 

  2. Tsujimoto Y, Shimizu S: Bcl-2 family: live or death switch. FEBS Lett 2000, 466:6–10.

    Article  PubMed  CAS  Google Scholar 

  3. Kitada S, Andersen J, Akar S, et al.: Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998, 91:3379–3389.

    PubMed  CAS  Google Scholar 

  4. Basanez G, Nechusht A, Drozhinin O, et al.: Bax, but not Bcl-xl, decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. Proc Natl Acad Sci U S A 1999, 96:5492–5497.

    Article  PubMed  CAS  Google Scholar 

  5. Tsukada N, Burger JA, Zvaifler NJ, et al.: Distinctive features of “nurse-like” cells that differentiate in the context of chronic lymphocytic leukemia. Blood 2002, 99:1030–1037.

    Article  PubMed  CAS  Google Scholar 

  6. Faderl S, Keating MJ, Do KA, et al.: Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). Leukemia 2002, 16:1045–1052. This paper involves a large trial demonstrating the prognostic importance of Bcl-2 in CLL.

    Article  PubMed  CAS  Google Scholar 

  7. Robertson LE, Plunkett W, McConnell K, et al.: Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia 1996, 10:456–459.

    PubMed  CAS  Google Scholar 

  8. Molica S, Dattilo A, Giulino C, et al.: Increased Bcl-2/ bax ratio in B-cell chronic lymphocytic leukemia is associated with a progressive pattern of disease. Haematologica 1998, 83:1122–1124.

    PubMed  CAS  Google Scholar 

  9. Nakayama K, Negishi I, Kuika K, et al.: Targeted disruption of Bcl-2— in mice: occurrence of gray hair, polycystic disease, and lymphocytopenia. Proc Natl Acad Sci U S A 1994, 91:3700–3704.

    Article  PubMed  CAS  Google Scholar 

  10. Park JR, Bernstein ID, Hockenbery DM: Primitive human haematopoietic precursors express Bcl-x but not Bcl-2. Blood 1995, 86:868–876.

    PubMed  CAS  Google Scholar 

  11. Pepper C, Hooper K, Thomas A, et al.: Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk Lymphoma 2001, 42:491–498.

    PubMed  CAS  Google Scholar 

  12. Jansen B, Wacheck V, Heere-Ress E, et al.: Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 2000, 356:1728–1733. This paper discusses a trial demonstrating the safety of Bcl-2 antisense therapy.

    Article  PubMed  CAS  Google Scholar 

  13. Rudin CM, Otterson GA, Mauer AM, et al.: A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 2002, 13:539–545.

    Article  PubMed  CAS  Google Scholar 

  14. Greco FA, Stroup SL, Gray JR, Hainsworth JD: Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer. J Clin Oncol 1996, 14:1642–1648.

    PubMed  CAS  Google Scholar 

  15. Chi KN, Gleave ME, Klasa R, et al.: A phase I dosefinding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormonerefractory prostate cancer. Clin Cancer Res 2001, 7:3920–3927.

    PubMed  CAS  Google Scholar 

  16. Waters JS, Webb A, Cunningham D, et al.: Phase I clinical and pharmacokinetic study of Bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2000, 18:1812–1823.

    PubMed  CAS  Google Scholar 

  17. Derenne S, Monia B, Dean NM, et al.: Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-xL is an essential survival protein of human myeloma cells. Blood 2002, 100:194–199.

    Article  PubMed  CAS  Google Scholar 

  18. Wang JL, Zhang ZJ, Choksi S, et al.: Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells. Cancer Res 2000, 60:1498–1502.

    PubMed  CAS  Google Scholar 

  19. Wang JL, Liu D, Zhang ZJ, et al.: Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci U S A 2000, 97:7124–7129.

    Article  PubMed  CAS  Google Scholar 

  20. Hu G, Khodadoust M, Konopleva M, et al.: Induction of apoptosis in lymphoid cell lines and primary CLL by HA14-1, a cell permeable organic small molecule that binds to the BH1 to BH3 surface pocket of bcl-2 protein. Am Assoc Cancer Res Abstracts 2002. http://www.aacr.org.

  21. Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001, 344:1031–1037.

    Article  PubMed  CAS  Google Scholar 

  22. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001, 344:1038–1042.

    Article  PubMed  CAS  Google Scholar 

  23. O’Gorman DM, McKenna SL, McGahon AJ, et al.: Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of P13-kinase survival signals. Leukemia 2000, 14:602–611.

    Article  PubMed  CAS  Google Scholar 

  24. Koh H, Lee KH, Kim D, et al.: Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factorinduced PRK2 cleavage. J Biol Chem 2000, 275:34451–34458.

    Article  PubMed  CAS  Google Scholar 

  25. Ashkenazi A, Pai RC, Fong S, et al.: Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999, 104:155–162.

    Article  PubMed  CAS  Google Scholar 

  26. Pedersen IM, Kitada S, Schimmer A, et al.: The triterpenoid CDDO induces apoptosis in refractory CLL Bcells. Blood 2002, 100:2965–2972.

    Article  PubMed  CAS  Google Scholar 

  27. Ito Y, Pandey P, Place A, et al.: The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism. Cell Growth Differ 2000, 11:261–267.

    PubMed  CAS  Google Scholar 

  28. Konopleva M, Tsao T, Ruvolo P, et al.: Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. Blood 2002, 99:326–335.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Burnham Institute, Room 6308, 10901 N. Torrey Pines Road, 92037, La Jolla, CA, USA

    Aaron D. Schimmer MD

Authors
  1. Aaron D. Schimmer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irene Munk-Pedersen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark D. Minden MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John C. Reed MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schimmer, A.D., Munk-Pedersen, I., Minden, M.D. et al. Bcl-2 and apoptosis in chronic lymphocytic leukemia. Curr. Treat. Options in Oncol. 4, 211–218 (2003). https://doi.org/10.1007/s11864-003-0022-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11864-003-0022-y

Keywords

Search

Navigation