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:

CLL

The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia

Leukemia volume 20, pages 77–81 (2006)Cite this article

Abstract

The G(-248)A polymorphism in the promoter region of the Bax gene was recently associated with low Bax expression, more advanced stage, treatment resistance and short overall survival in B-cell chronic lymphocytic leukemia (CLL), the latter particularly in treated patients. To investigate this further, we analyzed 463 CLL patients regarding the presence or absence of the G(-248)A polymorphism and correlated with overall survival, treatment status and known prognostic factors, for example, Binet stage, VH mutation status and genomic aberrations. In this material, similar allele and genotype frequencies of the Bax polymorphism were demonstrated in CLL patients and controls (n=207), where 19 and 21% carried this polymorphism, respectively, and no skewed distribution of the polymorphism was evident between different Binet stages and VH mutated and unmutated CLLs. Furthermore, no difference in overall survival was shown between patients displaying the G(-248)A polymorphism or not (median survival 85 and 102 months, respectively, P=0.21), and the polymorphism did not influence outcome specifically in treated CLL. Neither did the polymorphism affect outcome in prognostic subsets defined by VH mutation status or genomic aberrations. In conclusion, the pathogenic role and clinical impact of the Bax polymorphism is limited in CLL.

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

Similar content being viewed by others

References

  1. Aguilar-Santelises M, Rottenberg ME, Lewin N, Mellstedt H, Jondal M . Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression. Int J Cancer 1996; 69: 114–119.

    Article  CAS  PubMed  Google Scholar 

  2. McConkey DJ, Chandra J, Wright S, Plunkett W, McDonnell TJ, Reed JC et al. Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX. J Immunol 1996; 156: 2624–2630.

    CAS  PubMed  Google Scholar 

  3. Pepper C, Hoy T, Bentley DP . Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance. Br J Cancer 1997; 76: 935–938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schena M, Larsson LG, Gottardi D, Gaidano G, Carlsson M, Nilsson K et al. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells. Blood 1992; 79: 2981–2989.

    CAS  PubMed  Google Scholar 

  5. Faderl S, Keating MJ, Do KA, Liang SY, Kantarjian HM, O’Brien S et al. Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). Leukemia 2002; 16: 1045–1052.

    Article  CAS  PubMed  Google Scholar 

  6. Zha H, Aime-Sempe C, Sato T, Reed JC . Proapoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2. J Biol Chem 1996; 271: 7440–7444.

    Article  CAS  PubMed  Google Scholar 

  7. Saxena A, Viswanathan S, Moshynska O, Tandon P, Sankaran K, Sheridan DP . Mcl-1 and Bcl-2/Bax ratio are associated with treatment response but not with Rai stage in B-cell chronic lymphocytic leukemia. Am J Hematol 2004; 75: 22–33.

    Article  CAS  PubMed  Google Scholar 

  8. Saxena A, Moshynska O, Sankaran K, Viswanathan S, Sheridan DP . Association of a novel single nucleotide polymorphism, G(-248)A, in the 5′-UTR of BAX gene in chronic lymphocytic leukemia with disease progression and treatment resistance. Cancer Lett 2002; 187: 199–205.

    Article  CAS  PubMed  Google Scholar 

  9. Moshynska O, Moshynskyy I, Misra V, Saxena A . G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression. Oncogene 2005; 24: 2042–2049.

    Article  CAS  PubMed  Google Scholar 

  10. Starczynski J, Pepper C, Pratt G, Hooper L, Thomas A, Milligan D et al. Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic Leukemia once treatment is initiated. J Clin Oncol 2005; 23: 1514–1521.

    Article  CAS  PubMed  Google Scholar 

  11. Binet JL, Lepoprier M, Dighiero G, Charron D, D’Athis P, Vaugier G et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer 1977; 40: 855–864.

    Article  CAS  PubMed  Google Scholar 

  12. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.

    CAS  PubMed  Google Scholar 

  13. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK . Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.

    CAS  PubMed  Google Scholar 

  14. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  PubMed  Google Scholar 

  15. Jaffe ES, Harris NL, Stein H, Vardiman JW . World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001.

    Google Scholar 

  16. Li AH, Rosenquist R, Forestier E, Holmberg D, Lindh J, Löfvenberg E et al. Clonal rearrangements in childhood and adult precursor B acute lymphoblastic leukemia: a comparative polymerase chain reaction study using multiple sets of primers. Eur J Haematol 1999; 63: 211–218.

    Article  CAS  PubMed  Google Scholar 

  17. Li AH, Rosenquist R, Forestier E, Lindh J, Roos G . Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection. Leuk Res 2001; 25: 1033–1045.

    Article  CAS  PubMed  Google Scholar 

  18. Kröber A, Seiler T, Benner A, Bullinger L, Bruckle E, Lichter P et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002; 100: 1410–1416.

    PubMed  Google Scholar 

  19. Tobin G, Thunberg U, Johnson A, Eriksson I, Söderberg O, Karlsson K et al. Chronic lymphocytic leukemias utilizing the VH3–21 gene display highly restricted Vlambda2–14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. Blood 2003; 101: 4952–4957.

    Article  CAS  PubMed  Google Scholar 

  20. Tobin G, Thunberg U, Laurell A, Karlsson K, Åleskog A, Willander K et al. Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome. Haematologica 2005; 90: 465–469.

    CAS  PubMed  Google Scholar 

  21. Korz C, Pscherer A, Benner A, Mertens D, Schaffner C, Leupolt E et al. Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. Blood 2002; 99: 4554–4561.

    Article  CAS  PubMed  Google Scholar 

  22. Kienle DL, Korz C, Hosch B, Benner A, Mertens D, Habermann A et al. Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes. J Clin Oncol 2005; 23: 3780–3792.

    Article  CAS  PubMed  Google Scholar 

  23. el Rouby S, Thomas A, Costin D, Rosenberg CR, Potmesil M, Silber R et al. p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 1993; 82: 3452–3459.

    CAS  PubMed  Google Scholar 

  24. Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–1589.

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Drs Lars Klareskog and Leonid Padyukov and to the EIRA group for help with the collection of the normal control material. This study was supported by grants from the Swedish Cancer Society, Lion's Cancer Research Foundation, Uppsala, the research foundation of the Department of Oncology at Uppsala University, and Deutsche Krebshilfe (70-3183-Li1; Nr. 106116) and DFG STI 296/1-1.

Author information

Authors and Affiliations

  1. Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Å Skogsberg, G Tobin, C Sundström, H Jernberg-Wiklund, K Nilsson & R Rosenquist

  2. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    A Kröber, D Kienle, H Döhner & S Stilgenbauer

  3. Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden

    U Thunberg & A Laurell

  4. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    A Åleskog

  5. Department of Hematology, University Hospital, Linköping, Sweden

    K Karlsson

  6. Department of Medicine at Karolinska University Hospital, Huddinge, Sweden

    M Merup

  7. Department of Clinical Chemistry at Tampere University Hospital, Tampere, Finland

    J Vilpo

  8. Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden

    G Roos

Authors
  1. Å Skogsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Tobin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Kröber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Kienle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U Thunberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Åleskog
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Karlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Laurell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Merup
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Vilpo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C Sundström
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. G Roos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H Jernberg-Wiklund
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. K Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. S Stilgenbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. R Rosenquist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Rosenquist.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Skogsberg, Å., Tobin, G., Kröber, A. et al. The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia. Leukemia 20, 77–81 (2006). https://doi.org/10.1038/sj.leu.2404030

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404030

Keywords

This article is cited by

Search

Advanced search

Quick links