Association between multidrug resistance protein 4 polymorphism and adverse events in childhood acute lymphoblastic leukemia

Nonthaya Thangrua, Suradej Hongeng, Suntaree Apibal, Surakameth Mahasirimongkol, Ruchchadol Sawangpanich, Samart Pakakasama

Abstract


One of the major problems in treating childhood acute lymphoblastic leukemia (ALL) is 6-mercaptopurine (6-MP)-related toxicity, resulting from the accumulation of 6-thioguanine nucleotide (6-TGN) in cells. Multidrug resistance protein 4 (MRP4), a transport protein, plays an important role in the efflux of cytotoxic drugs, including toxic 6-TGN from cells. A single nucleotide polymorphism in human MRP4 rs3765534 C>T dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. The aim of this study was to investigate the association between MRP4 rs3765534 C>T genetic polymorphism and adverse events in Thai childhood ALL treated with 6-MP. The subjects were children less than 15 years of age who were diagnosed with ALL

at our institution between 2004 and 2007. They received 6-MP during induction, consoli- dation, and maintenance phases of therapy. The common 6-MP related toxicities were recorded. The polymorphism of MRP4 rs3765534 C>T was identified using real-time poly- merase chain reaction. The association between genetic variation and side effects of 6-MP was analyzed. A total of 186 children with ALL were included in this study. The genotyping showed 171 homozygous wild type (CC) and 15 heterozygous (CT) of this MRP4 polymorphism. The allele frequency of C and T alleles were 96% and 4%, respectively. Children with CT genotype were at risk of neutropenia during 6-MP exposure (OR = 3; 95% CI, 1.7-99.9; p = 0.03). Our study demonstrated that MRP4 rs3765534 T allele significantly increased risk of 6-MP related neutropenia in children with ALL.


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