Journal of Advances in Medical and Biomedical Research

en Assessment of TPMT Gene Polymorphisms and its Enzyme Activity in Pediatric Acute Lymphoblastic Leukemia Patients Receiving 6-Mercaptopurine: Correlation with Myelosuppression and Hepatotoxicity Medical Biology Medical Biology مقاله پژوهشی Original Research Article Background & Objective:  Thiopurine S-methyltransferase (TPMT) is a key enzyme in the metabolism of thiopurine drugs, including 6-mercaptopurine (6-MP). By methylating and inactivating 6-MP, TPMT regulates the accumulation of active metabolites and influences the risk of treatment-related toxicities, particularly myelosuppression. This study evaluated common TPMT polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C), plasma TPMT enzyme levels, and their associations with 6-MP-induced adverse effects in pediatric ALL patients.  Materials & Methods:  Ninety-eight patients with ALL receiving maintenance therapy with 6-MP under a standard-risk protocol were enrolled. TPMT*3B (460G>A) and TPMT*3C (719A>G) variants were analyzed by PCR-RFLP, while TPMT*2 (238G>C) was detected using allele-specific PCR. Sequencing was performed to confirm amplification of exons 7 and 10 in 19 samples each and exon 5 in two samples. Plasma TPMT enzyme levels were measured in 70 patients using ELISA. Associations between TPMT genotype, enzyme levels, and 6-MP-related toxicities, including leukopenia, neutropenia, and hepatotoxicity, were evaluated. Results:  The TPMT*3B variant was detected in one patient (allele frequency, 0.71%; heterozygous TPMT*3B/*1 genotype, 1.1%). No TPMT*2, TPMT*3A, TPMT*3C, or rare variants (TPMT*4, TPMT*7, TPMT*8, and TPMT*10) were identified. Sequencing confirmed the absence of these variants in the analyzed samples. Among the 70 patients assessed for TPMT activity, eight (11.4%) exhibited low enzyme levels. No significant association was observed between TPMT genotype and enzyme phenotype (P = 1.0). However, low TPMT enzyme levels were significantly associated with leukopenia (P = 0.04) and neutropenia (P = 0.02), but not hepatotoxicity (P = 0.12). Conclusion:  Low plasma TPMT enzyme activity was associated with an increased risk of 6-MP-induced myelosuppression in some patients with ALL. These findings suggest that assessment of TPMT enzyme activity, together with genotyping for common and rare TPMT variants, may improve prediction of thiopurine toxicity and support individualized 6-MP therapy. Acute Lymphoblastic Leukemia, Thiopurine Methyltransferase, Polymorphism, Pharmacogenetics, 6-Mercaptopurine, Leukopenia 238 250 http://journal.zums.ac.ir/browse.php?a_code=A-10-7480-1&slc_lang=en&sid=1 Saghar Zakeri Saghar.za@gmail.com 5200319475328460090741 5200319475328460090741 No Department of Medical and Molecular Genetics, Nobel Pathobiology and Genetics Laboratory, Isfahan, Iran Maryam Jafarian jfryanmaryam@gmail.com 5200319475328460090742 5200319475328460090742 No Department of Molecular Medicine and Genetics, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran Samin Alavi saminalavi@hotmail.com 5200319475328460090743 5200319475328460090743 No Pediatric Conjenital Hematologic Disorders Research Center, Research Institute of Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran Shahla Rahmani Shahlarahmani7075@gmail.com 5200319475328460090744 5200319475328460090744 No Department of Medical Laboratory Sciences, School of Allied Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran Yousef Mortazavi yousef1mortazavi@gmail.com 5200319475328460090745 5200319475328460090745 Yes Department of Molecular Medicine and Genetics, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran