Skip to main content

Advertisement

SpringerLink
Log in

Impact of ABCB1 Gene (C3435T/A2677G) Polymorphic Sequence Variations on the Outcome of Patients with Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Kashmiri Population: A Case–Control Study

  • Original Article
  • Published:
Indian Journal of Hematology and Blood Transfusion Aims and scope Submit manuscript

Abstract

Inherited polymorphic sequence variations in drug transport genes like ABCB1 impact a portion of patients with hematologic malignancies that show intrinsic or acquire resistance to treatment. Keeping in view inter-individual sensitivities for such drugs, we through this case–control study tested whether ABCB1 C3435T and G2677T polymorphisms have any influence on the risk and treatment response in patients with chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Genotyping for ABCB1 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism in 100 CML and 80 B-ALL patients along with 100 age and gender matched healthy controls. ABCB1 C3435T and G2677T polymorphism showed no association with CML. Genotype distribution revealed significant higher frequency of TT genotype for both SNPs in B-ALL cases and associated with increased B-ALL risk (OR 2.5, p = 0.04 for 3435TT; OR 2.4, p = 0.04 for 2677TT). There was no significant difference in genotype frequency of 3435C > T and 2677G > T among resistant and responsive groups for the two leukemia types. Kaplan–Meier survival plots revealed significantly lower event free survival in CML and B-ALL patients that were carriers of 3435TT genotype (p < 0.05). Multivariate analysis considered 3435TT genotype as independent risk factor for imatinib resistance in CML cases (HR 6.24, p = 0.002) and increased relapse risk in B-ALL patients (HR 4.51, p = 0.03). The current study provides preliminary evidence of a significant association between variant TT genotype and increased B-ALL risk. Also, results suggest that ABCB1 3435TT genotype increases imatinib resistance in CML and influence therapeutic outcome in B-ALL.

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

Similar content being viewed by others

References

  1. Tsuruo T, Naito M, Tomida A et al (2003) Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal. Cancer Sci 94:15–21

    Article  CAS  Google Scholar 

  2. Dimitris V, Volker D (2002) Challenges in treating hematologic malignancies. Semin Oncol 29:30–39

    Article  Google Scholar 

  3. Fouad A-D, Maha A-R, Muna I et al (2008) Polymorphisms of drug-metabolizing enzymes CYP1A1, GSTT and GSTP contribute to the development of diffuse large B-cell lymphoma risk in the Saudi Arabian population. Leukemia Lymphoma 9:122–129

    Google Scholar 

  4. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58

    Article  CAS  Google Scholar 

  5. Doyle LA, Yang W, Abruzzo LV et al (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95:15665–15670

    Article  CAS  Google Scholar 

  6. Robey RW, Shukla S, Steadman K et al (2007) Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure. Mol Cancer Ther 6:1877–1885

    Article  CAS  Google Scholar 

  7. Linsenmeyer ME, Jefferson S, Wolf M, Matthews JP, Board PG, Woodcock DM (1992) Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma. Br J Cancer 65:471–475

    Article  CAS  Google Scholar 

  8. Katayama K, Noguchi K, Sugimoto Y (2014) Regulations of P-glycoprotein/ABCB1/MDR1 in human cancer cells. New J Sci 2014:476974–1–476974–10

    Article  Google Scholar 

  9. Yasuhisa K, Shinya M, Michinori M, Kazumitsu U (2007) Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci 98:1303–1310

    Article  Google Scholar 

  10. Aller SG, Yu J, Ward A et al (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722

    Article  CAS  Google Scholar 

  11. Sakaeda T, Nakamura T, Okumura K (2003) Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmocodynamics of drugs. Pharmacogenomics 4:397–410

    Article  CAS  Google Scholar 

  12. Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33

    Article  CAS  Google Scholar 

  13. Breier A, Barancik M, Sulova Z, Uhrik B (2005) P-glycoprotein—implications of metabolism of neoplastic cells and cancer therapy. Curr Cancer Drug Targets 5:457–468

    Article  CAS  Google Scholar 

  14. Fromm MF (2002) The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 54:1295–1310

    Article  CAS  Google Scholar 

  15. Sheng X, Zhang L, Tong N et al (2012) MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case-control studies. Mol Biol Rep 39:7237–7249

    Article  CAS  Google Scholar 

  16. Dulucq S, Bouchet S, Turcq B et al (2008) Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 112:2024–2027

    Article  CAS  Google Scholar 

  17. Gregers J, Gréen H, Christensen IJ et al (2015) Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J 15:372–379

    Article  CAS  Google Scholar 

  18. Van Dongen JJM, Macintyre EA, Gabert JA, Delabesse E et al (1999) Standardized RT-PCR analysis of fusion gene transcripts from chromosomal aberrations in acute leukemia for detection of minimal residual disease. Leukemia 13:1910–1928

    Google Scholar 

  19. Baccarani M, Deininger MW, Rosti G et al (2013) European Leukaemia Net recommendations for the management of chronic myeloid leukaemia. Blood 122:872–884

    Article  CAS  Google Scholar 

  20. Smith M, Arthur D, Camitta B et al (1996) Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 14:18–24

    Article  CAS  Google Scholar 

  21. Derwich K, Wachowaik J, Zajac-spychala O et al (2011) Long term results in children with standard risk acute lymphoblastic leukemia treated with 5.0 gms/m2 vs 3.0 gms/m2 methotrexate i.e according to the modified ALL BFM 90 protocol. The report of Polish pediatric leukemia/lymphoma study. Mag Eur Med oncol 4:184

    Google Scholar 

  22. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL et al (2008) Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 111:5477–5485

    Article  CAS  Google Scholar 

  23. Azad NA, Shah ZA, Khan MS et al (2019) No role of 3435C > T and 2677G > T ABCB1 (MDR1) gene single nucleotide polymorphisms in imatinib treatment response: a case control study on CML patients of Kashmir. Meta Gene 19:1–276

    Article  Google Scholar 

  24. Elghannam DM, Ibrahim L, Ebrahim MA, Azmy E, Hakem H (2014) Association of MDR1 gene polymorphism (G2677T) with imatinib response in Egyptian chronic myeloid leukemia patients. Hematology 19:123–128

    Article  CAS  Google Scholar 

  25. Sailaja K, Surekha D, Rao DN, Raghunadharao D, Vishnupriya S (2010) Association of MDR1 gene polymorphism (G2677T) with chronic myeloid leukemia. Biol Med 2:17–21

    CAS  Google Scholar 

  26. Wang LH, Song YB, Zheng WL et al (2013) The association between polymorphisms in the MDR1 gene and risk of cancer: a systematic review and pooled analysis of 52 case–control studies. Cancer Cell Int 13:46–52

    Article  CAS  Google Scholar 

  27. Pawlik A, Baskiewicz-Masiuk M, Machalinski B et al (2005) Involvement of C3435T and G2677T multidrug resistance gene polymorphisms in release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. Eur J Pharmacol 528:27–36

    Article  CAS  Google Scholar 

  28. Pongstaporn W, Pakakasama S, Chaksangchaichote P, Pongtheerat T, Hongeng S, Permitr S (2015) MDR1 C3435T and C1236T polymorphisms: association with high-risk childhood acute lymphoblastic leukemia. Asian Pac J Cancer Prev 16:2839–2843

    Article  Google Scholar 

  29. Jamroziak K, Robak T (2004) Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies. Hematology 9:91–105

    Article  CAS  Google Scholar 

  30. Ni LN, Li JY, Miao KR et al (2010) Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol 28:265–269

    Article  Google Scholar 

  31. Panczyk M, Balcerczak E, Piaskowski S, Jamroziak K, Pasz- Walczak G, Mirowski M (2009) ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int J Colorectal Dis 24:895–905

    Article  Google Scholar 

  32. Tang K, Ngoi SM, Gwee PC et al (2002) Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 12:437–450

    Article  CAS  Google Scholar 

  33. Ghallab O, Hamed NAM, El Shafei S, Abo Elwafa R, Sherif S (2015) MDR1 gene polymorphism and outcome in Egyptian chronic myeloid leukaemia patients. J Cancer Biol Res 3:1062

    Google Scholar 

  34. Skoglund K, Moreno SB, Baytar M et al (2013) ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro. Pharmgenomics Pers Med 6:63–72

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Au A, Aziz Baba A, Goh AS et al (2014) Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients. Biomed Pharmacother 68:343–349

    Article  CAS  Google Scholar 

  36. Moulik NR, Parveen F, Kumar A et al (2014) Glutathione-S-transferase polymorphism and acute lymphoblastic leukemia (ALL) in north Indian children: a case-control study and meta-analysis. J Hum Genet 59:529–535

    Article  CAS  Google Scholar 

  37. Kim DH, Sriharsha L, Xu W et al (2009) Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res 15:4750–4758

    Article  CAS  Google Scholar 

  38. Megías-Vericat JE, Rojas L, Herrero MJ et al (2015) Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: a systematic review and meta-analysis of observational studies. Pharmacogenomics J 15(2):109–118

    Article  Google Scholar 

  39. Rao DN, Anuradha C, Vishnupriya S et al (2010) Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev 11:1063–1066

    PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the departments of Clinical Hematology and Medical Oncology, SKIMS for their support. We also acknowledge our patients for their participation in the study.

Funding

No funding was received for this work.

Author information

Author notes

  1. Shahid M. Baba and Arshad A. Pandith have contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Molecular Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K, 190011, India

    Shahid M. Baba & Zafar A. Shah

  2. Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K, India

    Arshad A. Pandith & Javid Rasool Bhat

  3. Department of Clinical Hematology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K, India

    Sajad A. Geelani

  4. Department of Basic Medical Sciences, College of Medicine, University of Bisha, Bisha, Kingdom of Saudi Arabia

    Mohammad Muzaffar Mir

  5. Department of Medical Oncology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, J&K, India

    Gul Mohammad Bhat

Authors
  1. Shahid M. Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arshad A. Pandith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zafar A. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sajad A. Geelani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Muzaffar Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Javid Rasool Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gul Mohammad Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SMB Conceptualized, designed and supervised the study. Did lab work and also drafted the manuscript. ZAS Supervised the study, provided the consumables and logistical support and submitted the manuscript. AAP Did proofreading and corrected the manuscript. MMM Did compilation and statistical work. JRB Provided patient samples. SAG Provided patient samples. GMB Provided patient samples.

Corresponding author

Correspondence to Zafar A. Shah.

Ethics declarations

Conflict of interest

The authors have no conflict of interest.

Ethics Approval

The study was approved by the local Institutional Ethics committee (IEC-SKIMS).

Consent to Participate

This study was conducted only after taking informed consent from all participants.

Consent for Publication

All the authors gave their consent for submission/publication of this manuscript.

Availability of Data and Materials

Data will be made available on request.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baba, S.M., Pandith, A.A., Shah, Z.A. et al. Impact of ABCB1 Gene (C3435T/A2677G) Polymorphic Sequence Variations on the Outcome of Patients with Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia in Kashmiri Population: A Case–Control Study. Indian J Hematol Blood Transfus 37, 21–29 (2021). https://doi.org/10.1007/s12288-020-01289-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12288-020-01289-6

Keywords

Search

Navigation