Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia.
Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia.
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NT5C2种系变异对急性淋巴细胞白血病儿童6-甲细胞嘌呤代谢的影响
DOI：
10.1002/cpt.2095
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发表时间：
2021-06
影响因子：
6.7
通讯作者：
Yang JJ
中科院分区：
文献类型：
--
作者：
Jiang C;Yang W;Moriyama T;Liu C;Smith C;Yang W;Qian M;Li Z;Tulstrup M;Schmiegelow K;Crews KR;Zhang H;Pui CH;Evans W;Relling M;Bhatia S;Yang JJ
6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide metabolites (TGN). Recent genome-wide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms (SNPs) nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to inter-patient variability in thiopurine drug disposition.
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影响因子：
30.8
作者：
Meyer, Julia A.;Wang, Jinhua;Hogan, Laura E.;Yang, Jun J.;Dandekar, Smita;Patel, Jay P.;Tang, Zuojian;Zumbo, Paul;Li, Sheng;Zavadil, Jiri;Levine, Ross L.;Cardozo, Timothy;Hunger, Stephen P.;Raetz, Elizabeth A.;Evans, William E.;Morrison, Debra J.;Mason, Christopher E.;Carroll, William L.
通讯作者：
Carroll, William L.
影响因子：
20.3
作者：
Barz, Malwine J.;Hof, Jana;Kirschner-Schwabe, Renate
通讯作者：
Kirschner-Schwabe, Renate
影响因子：
50.3
作者：
Dieck CL;Tzoneva G;Forouhar F;Carpenter Z;Ambesi-Impiombato A;Sánchez-Martín M;Kirschner-Schwabe R;Lew S;Seetharaman J;Tong L;Ferrando AA
通讯作者：
Ferrando AA
影响因子：
5.7
作者：
Moriyama, Takaya;Liu, Shuguang;Yang, Jun J.
通讯作者：
Yang, Jun J.
影响因子：
56.9
作者：
ELION, GB
通讯作者：
ELION, GB