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 Manuscript
  • Published:

Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy

Abstract

We investigated the prognostic significance of genetic polymorphism in glutathione-S transferase mu 1 (GSTM1), glutathione-S transferase theta 1 (GSTT1), NAD(P)H:quinone oxidoreductase (NQO1) and myeloperoxidase (MPO), the products of which are associated with drug metabolism as well as with detoxication, in 193 patients with de novo acute myeloid leukemia (AML) other than M3. Of the patients, 64.2% were either homozygous or heterozygous for GSTT1 (GSTT1+), while 35.8% showed homozygous deletions of GSTT1 (GSTT1). The GSTT1 group had a worse prognosis than the GSTT1+ group (P = 0.04), whereas other genotypes did not affect the outcome. Multivariate analysis revealed that GSTT1 was an independent prognostic factor for overall survival (relative risk: 1.53; P = 0.026) but not for disease-free survival of 140 patients who achieved complete remission (CR). The rate of early death after the initiation of chemotherapy was higher in the GSTT1 group than the GSTT1+ group (within 45 days after initial chemotherapy, P = 0.073; within 120 days, P = 0.028), whereas CR rates and relapse frequencies were similar. The null genotype of GSTT1 might be associated with increased toxicity after chemotherapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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. Appelbaum F . Molecular diagnosis and clinical decisions in adult acute leukemia Semin Hematol 1999 36: 401–410

    CAS  PubMed  Google Scholar 

  2. Lowenberg B, Downing J, Burnett A . Acute myeloid leukemia N Engl J Med 1999 341: 1051–1062

    Article  CAS  Google Scholar 

  3. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R . Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia Blood 1999 93: 3074–3080

    CAS  PubMed  Google Scholar 

  4. Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K, Takeshita A, Saito K, Hasegawa S, Shimodaira S, Tamura J, Shimazaki C, Matsue K, Kobayashi H, Arima N, Suzuki R, Morishita H, Saito H, Ueda R, Ohno R . Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho) Leukemia 1997 11: 1447–1452

    Article  CAS  Google Scholar 

  5. Baudard M, Beauchamp-Nicoud A, Delmer A, Rio B, Blanc C, Zittoun R, Marie JP . Has the prognosis of adult patients with acute myeloid leukemia improved over years? A single institution experience of 784 consecutive patients over a 16-year period Leukemia 1999 13: 1481–1490

    Article  CAS  Google Scholar 

  6. Boddy AV, Ratain MJ . Pharmacogenetics in cancer etiology and chemotherapy Clin Cancer Res 1997 3: 1025–1030

    CAS  PubMed  Google Scholar 

  7. Davies SM, Robison LL, Buckley JD, Radloff GA, Ross JA, Perentesis JP . Glutathione S-transferase polymorphisms in children with myeloid leukemia: a Children's Cancer Group study Cancer Epidemiol Biomarkers Prev 2000 9: 563–566

    CAS  PubMed  Google Scholar 

  8. Naoe T, Takeyama K, Yokozawa T, Kiyoi H, Seto M, Uike N, Ino T, Utsunomiya A, Maruta A, Jin-nai I, Kamada N, Kubota Y, Nakamura H, Shimazaki C, Horiike S, Kodera Y, Saito H, Ueda R, Wiemels J, Ohno R . Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1 and CYP3A4 in 469 Japanese patients with therapy-related leukemia/myelodysplastic syndrome and de novo acute myeloid leukemia Clin Cancer Res 2000 6: 4091–4095

    CAS  PubMed  Google Scholar 

  9. Ohno R, Kobayashi T, Tanimoto M, Hiraoka A, Imai K, Asou N, Tomonaga M, Tsubaki K, Takahashi I, Kodera Y, Yoshida M, Murakami H, Naoe T, Shimayama M, Tsukada T, Takeo T, Teshima H, Onozawa Y, Fujimoto K, Kuriyama K, Horiuchi A, Kimura I, Minami S, Miura Y, Kageyama H, Tahara T, Masaoka T, Shirakawa S, Saito H . Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia. AML-87 Study of the Japan Adult Leukemia Study Group Cancer 1993 71: 3888–3895

    Article  CAS  Google Scholar 

  10. Kobayashi T, Miyawaki S, Tanimoto M, Kuriyama K, Murakami H, Yoshida M, Minami S, Minato K, Tsubaki K, Ohmoto E, Oh H, Jinnai I, Sakamaki H, Hiraoka A, Kanamaru A, Takahashi I, Saito K, Naoe T, Yamada O, Asou N, Kageyama S, Emi N, Matsuoka A, Tomonaga M, Ohno R for the Japan Adult Leukemia Study Group. Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group J Clin Oncol 1996 14: 204–213

    Article  CAS  Google Scholar 

  11. Miyawaki S, Tanimoto M, Kobayashi T, Minami S, Tamura J, Omoto E, Kuriyama K, Hatake K, Saito K, Kanamaru A, Oh H, Ohtake S, Asou N, Sakamaki H, Yamada O, Jinnai I, Tsubaki K, Takeyama K, Hiraoka A, Matsuda S, Takahashi M, Shimazaki C, Adachi K, Kageyama S, Ohno R for the Japan Adult Leukemia Study Group. No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of adult acute myeloid leukemia: the JALSG-AML92 study. Japan Adult Leukemia Study Group Int J Hematol 1999 70: 97–104

    CAS  PubMed  Google Scholar 

  12. Cascorbi I, Henning S, Brockmoller J, Gephart J, Meisel C, Muller JM, Loddenkemper R, Roots I . Substantially reduced risk of cancer of the aerodigestive tract in subjects with variant-463A of the myeloperoxidase gene Cancer Res 2000 60: 644–649

    CAS  PubMed  Google Scholar 

  13. Wilce M, Parker M . Structure and function of glutathione S-transferases Biochim Biophys Acta 1994 1205: 1–18

    Article  CAS  Google Scholar 

  14. Hayes J, Pulford D . The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance Crit Rev Biochem Mol Biol 1995 30: 445–600

    Article  CAS  Google Scholar 

  15. Board PG . Biochemical genetics of glutathione-S-transferase in man Am J Hum Genet 1981 33: 36–43

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B, Taylor JB . Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism Biochem J 1994 300: 271–276

    Article  CAS  PubMed Central  Google Scholar 

  17. Rebbeck T . Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility Cancer Epidemiol Biomarkers Prev 1997 6: 733–743

    CAS  PubMed  Google Scholar 

  18. Hengstler JG, Arand M, Herrero ME, Oesch F . Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfotransferases: influence on cancer susceptibility Rec Res Cancer Res 1998 154: 47–85

    Article  CAS  Google Scholar 

  19. Strange R, Fryer A . The glutathione S-transferases: influence of polymorphism on cancer susceptibility IARC Sci Publ 1999 148: 231–249

    CAS  Google Scholar 

  20. Chen CL, Liu Q, Pui CH, Rivera GK, Sandlund JT, Ribeiro R, Evans WE, Relling MV . Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia Blood 1997 89: 1701–1707

    CAS  PubMed  Google Scholar 

  21. Chen H, Sandler DP, Taylor JA, Shore DL, Liu E, Bloomfield CD, Bell DA . Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect Lancet 1996 347: 295–297

    Article  CAS  Google Scholar 

  22. Preudhomme C, Nisse C, Hebbar M, Vanrumbeke M, Brizard A, Lai JL, Fenaux P . Glutathione S transferase theta 1 gene defects in myelodysplastic syndromes and their correlation with karyotype and exposure to potential carcinogens Leukemia 1997 11: 1580–1582

    Article  CAS  Google Scholar 

  23. Crump C, Chen C, Appelbaum FR, Kopecky KJ, Schwartz SM, Willman CL, Slovak ML, Weiss NS . Glutathione S-transferase theta 1 gene deletion and risk of acute myeloid leukemia Cancer Epidemiol Biomarkers Prev 2000 9: 457–460

    CAS  PubMed  Google Scholar 

  24. Davies SM, Robison LL, Buckley JD, Tjoa T, Woods WG, Radloff GA, Ross JA, Perentesis JP . Glutathione S-transferase polymorphisms and outcome of chemotherapy in childhood acute myeloid leukemia J Clin Oncol 2001 19: 1279–1287

    Article  Google Scholar 

  25. Howells RE, Redman CW, Dhar KK, Sarhanis P, Musgrove C, Jones PW, Alldersea J, Fryer AA, Hoban PR, Strange RC . Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer Clin Cancer Res 1998 4: 2439–2445

    CAS  PubMed  Google Scholar 

  26. Russo J, Russo I . Biological and molecular bases of mammary carcinogenesis Lab Invest 1987 57: 112–137

    CAS  Google Scholar 

  27. Wiencke J, Pemble S, Ketterer B, Kelsey K . Gene deletion ofglutathione S-transferase theta: correlation with induced genetic damage and potential role in endogenous mutagenesis Cancer Epidemiol Biomarkers Prev 1995 4: 253–259

    CAS  PubMed  Google Scholar 

  28. Kelsey KT, Wiencke JK, Ward J, Bechtold W, Fajen J . Sister-chromatid exchanges, glutathione S-transferase theta deletion and cytogenetic sensitivity to diepoxybutane in lymphocytes from butadiene monomer production workers Mutat Res 1995 335: 267–273

    Article  CAS  Google Scholar 

  29. Norppa H, Hirvonen A, Jarventaus H, Uuskula M, Tasa G, Ojajarvi A, Sorsa M . Role of GSTT1 and GSTM1 genotypes in determining individual sensitivity to sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes Carcinogenesis 1995 16: 1261–1264

    Article  CAS  Google Scholar 

  30. Pelin K, Hirvonen A, Norppa H . Influence of erythrocyte glutathione S-transferase T1 on sister chromatid exchanges induced by diepoxybutane in cultured human lymphocytes Mutagenesis 1996 11: 213–215

    Article  CAS  Google Scholar 

  31. Xu X, Wiencke JK, Niu T, Wang M, Watanabe H, Kelsey KT, Christiani DC . Benzene exposure, glutathione S-transferase theta homozygous deletion, and sister chromatid exchanges Am J Ind Med 1998 33: 157–163

    Article  CAS  Google Scholar 

  32. Hoban PR, Robson CN, Davies SM, Hall AG, Cattan AR, Hickson ID, Harris AL . Reduced topoisomerase II and elevated alpha class glutathione S-transferase expression in a multidrug resistant CHO cell line highly cross-resistant to mitomycin C Biochem Pharmacol 1992 43: 685–693

    Article  CAS  Google Scholar 

  33. Chao CC, Huang YT, Ma CM, Chou WY, Lin-Chao S . Overexpression of glutathione S-transferase and elevation of thiol pools in a multidrug-resistant human colon cancer cell line Mol Pharmacol 1992 41: 69–75

    CAS  PubMed  Google Scholar 

  34. Smith MT, Evans CG, Doane-Setzer P, Castro VM, Tahir MK, Mannervik B . Denitrosation of 1,3-bis(2-chloroethyl)-1-nitrosourea by class mu glutathione transferases and its role in cellular resistance in rat brain tumor cells Cancer Res 1989 49: 2621–2625

    CAS  PubMed  Google Scholar 

  35. Loe DW, Stewart RK, Massey TE, Deeley RG, Cole SP . ATP-dependent transport of aflatoxin B1 and its glutathione conjugates by the product of the multidrug resistance protein (MRP) gene Mol Pharmacol 1997 51: 1034–1041

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a Grant-in Aid (No. 9–2) from the Japanese Ministry of Health and Welfare. We are grateful to members of the Japan Adult Leukemia Study Group for providing patients’ samples. We also thank Ms Yoko Kudo for preparing the manuscript.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Naoe, T., Tagawa, Y., Kiyoi, H. et al. Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy. Leukemia 16, 203–208 (2002). https://doi.org/10.1038/sj.leu.2402361

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402361

Keywords

This article is cited by

Search

Quick links