Skip to main content

Advertisement

SpringerLink
Log in

Influence of BCL2-938C>A and BAX-248G>A promoter polymorphisms in the development of AML: case–control study from South India

  • Research Article
  • Published:
Tumor Biology

Abstract

B-cell lymphoma 2 (BCL2) and BCL2-associated X protein (BAX) proteins are anti-apoptotic and pro-apoptotic determinants of mitochondrial-mediated apoptosis, and their relative expression determines the cell fate. The promoter polymorphisms in these genes were shown to alter the protein function or expression and exert an impact on apoptosis regulation. Deregulation in the expression of any of these genes leads to disruption of cellular homeostasis and malignant transformation. The present study was aimed to determine the association of BCL2-938C>A and BAX-248G>A promoter polymorphisms with origin and progression of acute myeloid leukemia (AML). We also have performed combined genotype analysis to evaluate the cumulative effect of risk genotypes in the AML development. These polymorphisms were genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in 221 AML patients and 305 age- and sex-matched healthy controls. Our study revealed that BCL2-938CA (p = 0.018) and BAX-248GG (0.043) genotypes were significantly associated with increased risk for AML occurrence. BAX-248A allele had shown decreased risk for AML. The combined analysis had shown that BCL2-938CA+AA-BAX-248GG group had a 1.63-fold (95 % CI: 1.08–2.45, p = 0.02) increased risk for AML. None of the clinical variables had shown any significant association with both polymorphisms. With respect to complete remission (CR) rate, BAX-248GG genotype (p = 0.002) and G allele (p = 0.009) had conferred significant risk for complete remission failure. Although the log rank test was not significant, survival analysis had shown a trend where BCL2-938CA genotype, and BAX-248GG had reduced median disease-free survival (DFS) of 9 and 10 months, respectively. In conclusion, BCL2-938C>A and BAX-248G>A gene polymorphisms might contribute to the origin of AML. Moreover, influence of BAX-248GG genotype on CR and DFS rate suggests that the BAX-248G>A polymorphism can serve as marker for poor prognosis in AML.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nat Med. 1997;3:614–20.

    Article  CAS  PubMed  Google Scholar 

  2. Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2:647–56.

    Article  CAS  PubMed  Google Scholar 

  3. Kim TH, Zhao Y, Ding WX, Shin JN, He X, Seo YW, et al. Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release. Mol Biol Cell. 2004;15:3061–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Loro LL, Vintermyr OK, Liavaag PG, et al. Oral squamous cell carcinoma is associated with decreased bcl-2/bax expression ratio and increased apoptosis. Hum Pathol. 1999;30:1097–105.

    Article  CAS  PubMed  Google Scholar 

  5. Walter RB, Othus M, Burnett AK, Löwenberg B, Kantarjian HM, et al. Significance of FAB subclassification of “acute myeloid leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients. Blood. 2013;121(13):2424–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lahiri DK, Nurnberger Jr JI. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res. 1991;19(19):5444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hu Z, Chunying L, Kexin C, Li-E W, Erich MS, Margaret RS, et al. Single nucleotide polymorphisms in selected apoptotic genes and BPDE-induced apoptotic capacity in apparently normal primary lymphocytes: a genotype-phenotype correlation analysis. J Cancer Epidemiol. 2008;2008:147905.

    Article  PubMed  PubMed Central  Google Scholar 

  8. American cancer society http://www.cancer.org/cancer/leukemia-cutelymphocyticallinadults/overviewguide/leukemia-all-overview-survival-rates.

  9. Nuckel H, Frey UH, Bau M, Sellmann L, Stanelle J, Durig J, et al. Association of a novel regulatory polymorphism (-938 C>A) in the Bcl2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. Blood. 2007;109(1):290–7.

    Article  PubMed  Google Scholar 

  10. Seto M, Jaeger U, et al. Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma. Embo J. 1988;7(1):123–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Young RL, Korsmeyer SJ. A negative regulatory element in the bcl-2 5′-untranslated region inhibits expression from an upstream promoter. Mol Cell Biol. 1993;13(6):3686–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Banker DE, Radich J, Becker A, Kerkof K, Norwood T, Willman C, et al. The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. Clin Cancer Res. 1998;4(12):3051–62.

    CAS  PubMed  Google Scholar 

  13. Andreef M, Konopleva M. Mechanisms of drug resistance in AML. Cancer Treat Res. 2002;112:237–62.

    Article  Google Scholar 

  14. Del Poeta G, Adriano V, Maria IDP, Luca M, Francesco B, Anna T, et al. Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML). Clinical Observations, Interventions, and Therapeutic Trials. Blood. 2003;101(6).

  15. Venditti A, Del Poeta G, Maurillo L, Buccisano F, Del Principe MI, Mazzone C, et al. Combined analysis of bcl-2 and MDR1 proteins in 256 cases of acute myeloid leukemia. Haematologica. 2004;89(8).

  16. Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood. 1997;89(6):1845–53.

    CAS  PubMed  Google Scholar 

  17. Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, et al. Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo. Leukemia. 2000;14(9):1606–13.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang N, Li X, Tao K, Jiang L, Ma T, Yan S, et al. BCL-2(-938C>A) polymorphism is associated with breast cancer susceptibility. BMC Med Genet. 2011;12:48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Moon JH, Sohn SK, Lee MH, Jang JH, Kim K, Jung CW, et al. BCL2 gene polymorphism could predict the treatment outcomes in acute myeloid leukemia patients. Leuk Res. 2010;34:166–72.

    Article  CAS  PubMed  Google Scholar 

  20. Apte SS, Mattei MG, Olsen BR. Mapping of the human BAX gene to chromosome 19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, BAX delta. Genomics. 1995;26(3):592–4.

    Article  CAS  PubMed  Google Scholar 

  21. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human Bax gene. Cell. 1995;80:293–9.

    Article  CAS  PubMed  Google Scholar 

  22. Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995;270(5233):96–9.

    Article  CAS  PubMed  Google Scholar 

  23. Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al. Somatic frame shift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997;275:967–9.

    Article  CAS  PubMed  Google Scholar 

  24. Meijerink JPP, Mensink EJBM, Wang K, Sedlak TW, Sloetjes AW, de Witte T, et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood. 1998;91:2991–7.

    CAS  PubMed  Google Scholar 

  25. Saxena A, Moshynska O, Sankaran K, et al. 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 

  26. 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(7):1514–21.

    Article  CAS  PubMed  Google Scholar 

  27. Skogsberg S, Tobin G, Krober A, Kienle D, Thunberg U, 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. 2006;20:77–81.

    Article  CAS  PubMed  Google Scholar 

  28. Zintzaras E, Kitsios GD. Synopsis and synthesis of candidate-gene association studies in chronic lymphocytic leukemia: the CUMAGAS-CLL information system. Am J Epidemiol. 2009;170(6):671–8.

    Article  PubMed  Google Scholar 

  29. Bakirov BA, Karimov DO, Viktorova TV. Polymorphism of apoptosis regulatory and growth factor genes in patients with chronic lymphocytic leukemia. Russ Open Med J. 2012;1:0101.

    Article  Google Scholar 

  30. Enjuanes A, Benavente Y, Bosch F, et al. Genetic variants in apoptosis and immunoregulation-related genes are associated with risk of chronic lymphocytic leukemia. Cancer Res. 2008;68:10178–86.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We sincerely acknowledge all the subjects and healthy volunteers for participating in the study. We would like to thank the Nizam’s Institute of Medical Sciences, Hyderabad for providing samples and clinical data of the AML patients.

Funding

University Grants Commission, New Delhi, India has supported this study by providing financial assistance (EMERITUS-2012-13-GEN-569/SA-II) to VS through the Emeritus fellowship, and the Indian Council for Medical Research (ICMR), New Delhi, had encouraged AC to carry out this work by awarding SRF.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Genetics, Osmania University, Hyderabad, 500007, India

    Anuradha Cingeetham, Sugunakar Vuree, Manjula Gorre, Santhoshi Rani Nanchari, Prajitha Mohandas Edathara, Phannibhushann Meka, Sandhya Annamaneni & Vishnupriya Satti

  2. Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, 530053, India

    Raghunadharao Digumarthi

  3. MNJ Institute of Oncology Regional Cancer Center, Hyderabad, India

    Sudha Sinha

  4. School of Chemical and Biotechnology, SASTRA University, Thanjuvur, India

    Nageswara Rao Dunna

Authors
  1. Anuradha Cingeetham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sugunakar Vuree
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nageswara Rao Dunna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manjula Gorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Santhoshi Rani Nanchari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Prajitha Mohandas Edathara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Phannibhushann Meka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sandhya Annamaneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Raghunadharao Digumarthi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sudha Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vishnupriya Satti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vishnupriya Satti.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cingeetham, A., Vuree, S., Dunna, N.R. et al. Influence of BCL2-938C>A and BAX-248G>A promoter polymorphisms in the development of AML: case–control study from South India. Tumor Biol. 36, 7967–7976 (2015). https://doi.org/10.1007/s13277-015-3457-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3457-4

Keywords

Search

Navigation