Skip to main content

Advertisement

SpringerLink
Log in

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

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
Fig. 3

Similar content being viewed by others

References

  1. Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer. 2011;2:95–107.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, European LeukemiaNet, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.

    Article  PubMed  Google Scholar 

  3. Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, et al. A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood. 2011;117:2366–72.

    Article  CAS  PubMed  Google Scholar 

  4. Bullinger L, Döhner K, Bair E, Fröhling S, Schlenk RF, Tibshirani R, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med. 2004;350:1605–16.

    Article  CAS  PubMed  Google Scholar 

  5. Sakamaki H, Miyawaki S, Ohtake S, Emi N, Yagasaki F, Mitani K, et al. Allogeneic stem cell transplantation versus chemotherapy as post-remission therapy for intermediate or poor risk adult acute myeloid leukemia: results of the JALSG AML97 study. Int J Hematol. 2010;91:284–92.

    Article  PubMed  Google Scholar 

  6. Naoe T, Kiyoi H. Gene mutations of acute myeloid leukemia in the genome era. Int J Hematol. 2013;97:165–74.

    Article  CAS  PubMed  Google Scholar 

  7. Krivtsov AV, Figueroa ME, Sinha AU, Stubbs MC, Feng Z, Valk PJ, et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia. 2013;27:852–60.

    Article  CAS  PubMed  Google Scholar 

  8. Wiley JS, Jones SP, Sawyer WH, Paterson AR. Cytosine arabinoside influx and nucleoside transport sites in acute leukemia. J Clin Investig. 1982;69:479–89.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Schröder JK, Seidelmann M, Kirch HC, Seeber S, Schütte J. Assessment of resistance induction to cytosine arabinoside following transfer and overexpression of the deoxycytidylate deaminase gene in vitro. Leuk Res. 1998;22:619–24.

    Article  PubMed  Google Scholar 

  10. Whelan J, Smith T, Phear G, Rohatiner A, Lister A, Meuth M. Resistance to cytosine arabinoside in acute leukemia: the significance of mutations in CTP synthetase. Leukemia. 1994;8:264–5.

    CAS  PubMed  Google Scholar 

  11. Gamazon ER, Lamba JK, Pounds S, Stark AL, Wheeler HE, Cao X, et al. Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients. Blood. 2013;121:4366–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Mahlknecht U, Dransfeld CL, Bulut N, Kramer M, Thiede C, Ehninger G, et al. SNP analyses in cytarabine metabolizing enzymes in AML patients and their impact on treatment response and patient survival: identification of CDA SNP C-451T as an independent prognostic parameter for survival. Leukemia. 2009;23:1929–32.

    Article  CAS  PubMed  Google Scholar 

  13. Kim KI, Huh IS, Kim IW, Park T, Ahn KS, Yoon SS, et al. Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients. Eur J Cancer. 2013;49:403–10.

    Article  CAS  PubMed  Google Scholar 

  14. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    Article  CAS  PubMed  Google Scholar 

  15. Rha SY, Jeung HC, Choi YH, Yang WI, Yoo JH, Kim BS, et al. An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients. Oncologist. 2007;12:622–30.

    Article  CAS  PubMed  Google Scholar 

  16. Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Annal Statist. 1988;16:1141–54.

    Article  Google Scholar 

  17. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. Am Statist Assoc. 1999;94:496–509.

    Article  Google Scholar 

  18. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Verschuur AC, van Gennip AH, Leen R, Voûte PA, van Kuilenburg AB. Cyclopentenyl cytosine increases the phosphorylation and incorporation into dna of arabinofu-ranosyl cytosine in a myeloid leukemic cell-line. Adv Exp Med Biol. 2000;486:311–7.

    CAS  PubMed  Google Scholar 

  20. Verschuur AC, Brinkman J, Van Gennip AH, Leen R, Vet RJ, Evers LM, et al. Cyclopentenyl cytosine induces apoptosis and increases cytarabine-induced apoptosis in a T-lymphoblastic leukemic cell-line. Leuk Res. 2001;25:891–900.

    Article  CAS  PubMed  Google Scholar 

  21. Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, et al. Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res. 2006;12:1794–803.

    Article  CAS  PubMed  Google Scholar 

  22. Gati WP, Paterson AR, Larratt LM, Turner AR, Belch AR. Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein. Blood. 1997;90:346–53.

    CAS  PubMed  Google Scholar 

  23. Kim SR, Saito Y, Maekawa K, Sugiyama E, Kaniwa N, Ueno H, et al. Thirty novel genetic variations in the SLC29A1 gene encoding human equilibrative nucleoside transporter 1 (hENT1). Drug Metab Pharmacokinet. 2006;21:248–56.

    Article  CAS  PubMed  Google Scholar 

  24. Suzuki Y, Homma M, Abei M, Hyodo I, Kohda Y. Impact of solute carrier family 29 member 1 (SLC29A1) single nucleotide polymorphisms on mRNA expression in peripheral blood mononuclear cells. Biol Pharm Bull. 2013;36:144–6.

    Article  CAS  PubMed  Google Scholar 

  25. Myers SN, Goyal RK, Roy JD, Fairfull LD, Wilson JW, Ferrell RE. Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1. Pharmacogenet Genom. 2006;16:315–20.

    Article  CAS  Google Scholar 

  26. Capizzi RL, Yang JL, Cheng E, Bjornsson T, Sahasrabudhe D, Tan RS, et al. Alteration of the pharmacokinetics of high-dose ara-C by its metabolite, high ara-U in patients with acute leukemia. J Clin Oncol. 1983;1:763–71.

    CAS  PubMed  Google Scholar 

  27. Pérez-Torras S, García-Manteiga J, Mercadé E, Casado FJ, Carbó N, Pastor-Anglada M, et al. Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT1) enhances gemcitabine response in human pancreatic cancer. Biochem Pharmacol. 2008;76:322–9.

    Article  PubMed  Google Scholar 

  28. Braess J, Pförtner J, Kern W, Hiddemann W, Schleyer E. Cytidine deaminase—the methodological relevance of AraC deamination for ex vivo experiments using cultured cell lines, fresh leukemic blasts, and normal bone marrow cells. Ann Hematol. 1999;78:514–20.

    Article  CAS  PubMed  Google Scholar 

  29. Cao X, Mitra AK, Pounds S, Crews KR, Gandhi V, Plunkett W, et al. RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients. Pharmacogenomics. 2013;14:1449–66.

    Article  CAS  PubMed  Google Scholar 

  30. Falk IJ, Fyrberg A, Paul E, Nahi H, Hermanson M, Rosenquist R, et al. Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5′-nucleotidase. Am J Hematol. 2013;88:1001–6.

    Article  CAS  PubMed  Google Scholar 

  31. Carpi FM, Vincenzetti S, Ubaldi J, Pucciarelli S, Polzonetti V, et al. CDA gene polymorphisms and enzyme activity: genotype–phenotype relationship in an Italian-Caucasian population. Pharmacogenomics. 2013;14:769–81.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the all physicians and nurses at the Hematology and Oncology Department of Tokai University Hospital and laboratory staff in the Department of Hematology and Oncology at Tokai University for their kind support; particularly T. I., E. M., and N. S. for assitance with the genotyping. We also appreciate valuable advice regarding this study from the Morishima research group on Allergic Disease and Immunology from the Ministry of Health, Labor, and Welfare of Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Internal Medicine, Tokai University School of Medicine, 143 shimokasuya, Isehara, Kanagawa, 259-1143, Japan

    Jun Amaki, Makoto Onizuka, Ken Ohmachi, Yasuyuki Aoyama, Ryujiro Hara, Akifumi Ichiki, Hidetsugu Kawai, Ai Sato, Mitsuki Miyamoto, Masako Toyosaki, Shinichiro Machida, Minoru Kojima, Yukari Shirasugi, Hiroshi Kawada, Yoshiaki Ogawa & Kiyoshi Ando

Authors
  1. Jun Amaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Onizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ken Ohmachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuyuki Aoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryujiro Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akifumi Ichiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidetsugu Kawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ai Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mitsuki Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masako Toyosaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shinichiro Machida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Minoru Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yukari Shirasugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroshi Kawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yoshiaki Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kiyoshi Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Onizuka.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amaki, J., Onizuka, M., Ohmachi, K. et al. Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy. Int J Hematol 101, 543–553 (2015). https://doi.org/10.1007/s12185-015-1766-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-015-1766-4

Keywords

Search

Navigation