The T_T genotype within the NME1 promoter single nucleotide polymorphism −835 C/T is associated with an increased risk of cytarabine induced neurotoxicity in patients with acute myeloid leukemia

Abstract

Recently, numerous studies have been published on inter-individual variations in the response to specific treatment with cytostatic agents such as cytarabine (Ara-C) in patients with acute myeloid leukemia (AML). Differences at the genetic level and potentially associated changes in the expression and/or function of specific drug metabolizing enzymes appear to play an important role in this inter-individual susceptibility. Single nucleotide polymorphisms (SNPs) can be easily assessed in order to further investigate and explain inter-individual differences as to Ara-C associated toxicity and response to treatment. In this retrospective study we correlated five SNPs within the NME1 promoter with drug-induced toxicity, disease-free survival and overall survival (OS) in 360 Caucasian patients suffering from AML. A significant correlation between SNPs and disease-free survival or overall survival was not found. For the NME1 promoter SNP − 835 C/T (rs2302254) we identified a significant correlation between low platelet counts and better Eastern Cooperative Oncology Group performance status (grade 3/4). An increased risk of neurotoxicity was identified for the NME1 promoter SNP − 835 C/T (rs2302254) genotype T_T. Multivariate analyses also showed that these variables were independent risk factors. Ara-C causes neuronal cell death by introduction of apoptosis with reactive oxygen species, causing oxidative DNA damage and initiating the p53-dependent apoptotic program. Recent data show that oral administration of the antioxidant N-acetylcysteine for 14 days is able to prevent Ara-C induced behavioral deficits and cellular alterations of the adult cerebellum in a rat model.

Keywords::

• Myeloid leukemias and dysplasias
• molecular genetics
• genetic and other predisposing conditions

Acknowledgements

The contribution of all physicians and patients in the AML96 treatment trial of the SAL (Studien Alliance Leukämie) is highly appreciated. This work was supported by grants from the Deutsche José Carreras Leukämie-Stiftung e. V. (DJCLS R 09/20) to U.M.

Potential conflict of interest:

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