Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia
Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia
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DOI：
10.1182/blood-2008-11-191098
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发表时间：
2009-08-13
期刊：
影响因子：
20.3
通讯作者：
Krajinovic, Maja
中科院分区：
文献类型：
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作者：
Ansari, Marc;Sauty, Geraldine;Krajinovic, Maja
甲氨蝶呤和6-巯基嘌呤是治疗急性淋巴细胞白血病的重要成分，是多药耐药相关蛋白MRP4的底物。分析了MRP4基因的8个单核苷酸多态，发现4个变异体为标签SNPs，频率大于或等于5%。对275例急性淋巴细胞白血病儿童的治疗反应与它们的相关性进行了研究。调节性T-1393C多态的TC基因型与较好的无事件生存率(P=0.02)和较低的甲氨蝶呤血浆浓度(P=0.01)相关。A934C(Lys304Asn)替换的CA基因型与较低的无事件生存率(P=0.02)和较高的高度血小板减少发生率(P=0.01)相关。基因报告分析表明，C-1393等位基因唯一标记的启动子单倍型比其余单倍型具有更高的启动子活性(P<；.001)。需要进一步的分析来复制这项初步研究，并更深入地了解这些多态的功能影响。(血。2009；114：1383-1386)
Methotrexate and 6-mercaptopurine, important components of acute lymphoblastic leukemia treatment, are substrates for multidrug resistance-associated protein MRP4. Eight single nucleotide polymorphisms were analyzed in MRP4 gene, and 4 variants were identified as tagSNPs with frequency more than or equal to 5%. They were investigated for association with treatment responses in 275 children with acute lymphoblastic leukemia. The TC genotype of the regulatory T-1393C polymorphism was associated with better event-free survival (P =.02) and lower methotrexate plasma levels (P = .01). The CA genotype of A934C (Lys304Asn) substitution correlated in contrast with lower event-free survival (P = .02) and higher frequency of high-grade thrombocytopenia (P = .01). Gene reporter assay showed that the promoter haplotype uniquely tagged by the C-1393 allele conferred higher promoter activity compared with remaining haplotypes (P < .001). Further analyses are needed to replicate this pilot study and get closer insight into the functional effect of these polymorphisms. (Blood. 2009;114:1383-1386)