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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 volume 23, pages 1929–1932 (2009)Cite this article

Cytarabine (Ara-C) is the most important element of standard acute myeloid leukemia (AML) treatment regimens since more than 40 years. However, response to Ara-C treatment is marked by significant inter-individual differences and the development of Ara-C resistance is still a major drawback. Differences in DNA sequences, such as single nucleotide polymorphisms (SNPs), may affect the expression and/or function of specific drug protein targets and explain, at least in part, the inter-individual variations in the response to specific treatments.

In this study, we identified and correlated SNPs of these three critical enzymes within the Ara-C metabolic pathway with drug-induced toxicity and 5-year overall survival (OS) in 360 caucasian AML patients. All the patients were treated within the multicenter trial AML96 of the German Study Initiative Leukemia (DSIL) between 1996 and 2003 (patient characteristics: Table 1). Median observation time was 6.2 (4.3–9.0) years. AML FAB-M3 (acute promyelocytic leukemia (APL)) patients were not included and treated in other European trials.

Table 1 AML patient characteristics
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References

  1. Stam RW, den Boer ML, Meijerink JP, Ebus ME, Peters GJ, Noordhuis P et al. Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. Blood 2003; 101: 1270–1276.

    Article  CAS  Google Scholar 

  2. Coleman CN, Stoller RG, Drake JC, Chabner BA . Deoxycytidine kinase: properties of the enzyme from human leukemic granulocytes. Blood 1975; 46: 791–803.

    CAS  PubMed  Google Scholar 

  3. Schaich M, Ritter M, Illmer T, Lisske P, Thiede C, Schakel U et al. Mutations in ras proto-oncogenes are associated with lower mdr1 gene expression in adult acute myeloid leukaemia. Br J Haematol 2001; 112: 300–307.

    Article  CAS  Google Scholar 

  4. Gramatzki M, Ludwig WD, Burger R, Moos P, Rohwer P, Grunert C et al. Antibodies TC-12 (‘unique’) and TH-111 (CD96) characterize T-cell acute lymphoblastic leukemia and a subgroup of acute myeloid leukemia. Exp Hematol 1998; 26: 1209–1214.

    CAS  PubMed  Google Scholar 

  5. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    Article  CAS  Google Scholar 

  6. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107: 4011–4020.

    Article  CAS  Google Scholar 

  7. Mohr B, Bornhauser M, Thiede C, Schakel U, Schaich M, Illmer T et al. Comparison of spectral karyotyping and conventional cytogenetics in 39 patients with acute myeloid leukemia and myelodysplastic syndrome. Leukemia 2000; 14: 1031–1038.

    Article  CAS  Google Scholar 

  8. Smigielski EM, Sirotkin K, Ward M, Sherry ST . dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res 2000; 28: 352–355.

    Article  CAS  Google Scholar 

  9. The International HapMap Project. Nature 2003; 426: 789–796.

  10. De La Vega FM, Dailey D, Ziegle J, Williams J, Madden D, Gilbert DA . New generation pharmacogenomic tools: a SNP linkage disequilibrium Map, validated SNP assay resource, and high-throughput instrumentation system for large-scale genetic studies. Biotechniques 2002, Suppl: 48–50, 52, 54.

  11. Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa R, Maekawa K et al. Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol 2007; 25: 32–42.

    Article  CAS  Google Scholar 

  12. Fitzgerald SM, Goyal RK, Osborne WR, Roy JD, Wilson JW, Ferrell RE . Identification of functional single nucleotide polymorphism haplotypes in the cytidine deaminase promoter. Hum Genet 2006; 119: 276–283.

    Article  CAS  Google Scholar 

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Acknowledgements

The contribution of all physicians and patients in the AML96 treatment trial of the DSIL (Deutsche Studieninitiative Leukämie) is highly appreciated. This work was supported by grants from the Deutsche José Carreras Leukämie-Stiftung eV (DJCLS R 05/11), the Deutsche Forschungsgemeinschaft (MA 2057/2-4) and the Dietmar Hopp Foundation (Heidelberg) to UM.

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Authors and Affiliations

  1. Saarla,

    U Mahlknecht & C-L Dransfeld

  2. Department of Internal Medicine, Division of Immunotherapy and Gene Therapy, nd University Medical Center, José Carreras Research Center, Homburg/Saar, Germany

    U Mahlknecht & C-L Dransfeld

  3. Department of Hematology/Oncology, University of Heidelberg Medical Center, Heidelberg, Germany

    U Mahlknecht, C-L Dransfeld & N Bulut

  4. Department of Internal Medicine I, University of Dresden, Dresden, Germany

    M Kramer, C Thiede, G Ehninger & M Schaich

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  1. U Mahlknecht
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  2. C-L Dransfeld
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  4. M Kramer
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  6. G Ehninger
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  7. M Schaich
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Correspondence to U Mahlknecht.

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Mahlknecht, U., Dransfeld, CL., Bulut, N. 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 23, 1929–1932 (2009). https://doi.org/10.1038/leu.2009.113

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