Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects.

6-Mercaptopurine (6-MP) plays an important role in treatment of childhood acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphohydrolase (ITPA) is an enzyme involved in 6-MP metabolic pathway that convert the inosine triphosphate (ITP) to inosine monophosphate (IMP) and prevents the accumulation of the toxic metabolite ITP. Our objective was to evaluate the ITPA 94C>A, IVS2+21A>C polymorphisms in patients with ALL treated with 6-MP and prediction of its clinical outcomes. Our study population consisted of 70 patients diagnosed with ALL in the Division of Hematology-Oncology of Tehran Mofid Hospital. PCR was carried out to amplify exon 2, exon 3, intron 2, and intron 3 of ITPA gene then, all the amplified fragments were subjected to directional sequencing and then association between genotype and 6-MP toxicity was studied. In this study two exonic variants including 94C>A and 138G>A showed a prevalence of 8.5% and 36.4%, respectively. Two intronic variants, IVS2+21A>C and IVS3+101G>A were found in 13.5% and 7% of the samples, respectively. The rate of myelosuppression in the presence of mutant homozygote and heterozygous alleles (94C>A, 138G>A, IVS2+21A>C and IVS3+101G>A) was higher than that of wild type alleles during the use of 6-MP. Hepatotoxicity in patients with mutant homozygous and heterozygous 94C>A and IVS3+101G>A during the treatment 6-MP was higher than before treatment with 6-MP. Our results showed that patients with aberrant ITPase genotype (mutant homozygous or heterozygous), more likely to be myelosuppressed and show liver toxicity after treatment with 6-MP. Our results suggest that pre-therapeutic screening of patients for ITPA 94C>A, IVS2+21A>C and IVS3+101G>A can help in minimizing the adverse effects of 6-MP in ALL patients.