Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms.
Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms.
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DOI：
10.1038/s41375-018-0190-1
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发表时间：
2018-12
期刊：
影响因子：
11.4
通讯作者：
Kato M
中科院分区：
文献类型：
--
作者：
Tsujimoto S;Osumi T;Uchiyama M;Shirai R;Moriyama T;Nishii R;Yamada Y;Kudo K;Sekiguchi M;Arakawa Y;Yoshida M;Uchiyama T;Terui K;Ito S;Koh K;Takita J;Ito E;Tomizawa D;Manabe A;Kiyokawa N;Yang JJ;Kato M
硫嘌呤是治疗儿童和成人急性淋巴细胞白血病（ALL）和淋巴母细胞淋巴瘤（LBL）的关键，6-巯基嘌呤（6-MP）常用于巩固和维持治疗[1-3]。白细胞减少症是6-MP的剂量限制性毒性，部分原因是TPMT的亚型变体[2-5]，TMPT基因分型的临床重要性已得到充分证实。最近，NUDT 15被鉴定为一种新的硫嘌呤调节剂，在亚洲人和西班牙人中最显著地赋予6-MP敏感性[4-9]。具有双等位基因NUDT 15变体的患者对6-MP极其敏感，并且仅标准剂量的5-10%就足以维持目标白细胞计数[4，8]。到目前为止，已经鉴定了NUDT 15中总共7种具有低二磷酸酶活性的变体，导致6-MP过度骨髓抑制[4，10，11]，并且已知存在具有不同变体组合的单倍型（图1a）。考虑到NUDT 15基因分型对6-MP个体化给药的临床重要性[6，12]，应精确确定二倍体型，尤其是对于在多个变体处具有杂合基因型的患者。例如，一例杂合子c。36_37insGGAGTC和c. 415 C> T是最常见的组合[4]，应确定为复合杂合性（* 3/* 6）或单等位基因变体（* 1/* 2），因为两种二倍体对总NUDT 15活性具有显著不同的影响[4]。
Thiopurines are key to the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in children and adults, and 6-mercaptopurine (6-MP) is commonly used in consolidation and maintenance therapy [1–3]. Leukopenia is a dose-limiting toxicity of 6-MP partly explained by hypomorphic variants of TPMT [2–5] and clinical importance of TMPT genotyping is well established. Recently, NUDT15 was identified as a novel thiopurine regulator conferring 6-MP sensitivity most prominently in Asians and Hispanics [4–9]. Patients with bi-allelic NUDT15 variants are extremely sensitive to 6-MP, and only 5–10% of the standard dose is sufficient to maintain the target leukocyte count [4, 8]. Thus far, a total of seven variants in NUDT15 with low diphosphatase activity resulting in excess myelosuppression by 6-MP have been identified [4, 10, 11] and haplotypes with different combinations of variants are known to exist (Fig. 1a). Given the clinical importance of NUDT15 genotyping for individualized dosing of 6-MP [6, 12], the diplotype should be precisely determined, especially for those with heterozygous genotype at multiple variants. For example, a case with heterozygous c. 36_37insGGAGTC and c. 415C> T, which is the most frequent combination [4], should be determined as compound heterozygosity (* 3/* 6) or mono-allelic variants (* 1/* 2), because the two diplotypes have significantly different impacts on total NUDT15 activity [4].
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影响因子：
30.8
作者：
Yang SK;Hong M;Baek J;Choi H;Zhao W;Jung Y;Haritunians T;Ye BD;Kim KJ;Park SH;Park SK;Yang DH;Dubinsky M;Lee I;McGovern DP;Liu J;Song K
通讯作者：
Song K
影响因子：
30.8
作者：
Moriyama, Takaya;Nishii, Rina;Perez-Andreu, Virginia;Yang, Wenjian;Klussmann, Federico Antillon;Zhao, Xujie;Lin, Ting-Nien;Hoshitsuki, Keito;Nersting, Jacob;Kihira, Kentaro;Hofmann, Ute;Komada, Yoshihiro;Kato, Motohiro;McCorkle, Robert;Li, Lie;Koh, Katsuyoshi;Najera, Cesar Rolando;Kham, Shirley Kow-Yin;Isobe, Tomoya;Chen, Zhiwei;Chiew, Edwynn Kean-Hui;Bhojwani, Deepa;Jeffries, Cynthia;Lu, Yan;Schwab, Matthias;Inaba, Hiroto;Pui, Ching-Hon;Relling, Mary V.;Manabe, Atsushi;Hori, Hiroki;Schmiegelow, Kjeld;Yeoh, Allen E. J.;Evans, William E.;Yang, Jun J.
通讯作者：
Yang, Jun J.
影响因子：
5.3
作者：
Hidaka, Noriko;Iwama, Eiji;Nakanishi, Yoichi
通讯作者：
Nakanishi, Yoichi
影响因子：
2.8
作者：
Liang, D-C;Yang, C-P;Shih, L-Y
通讯作者：
Shih, L-Y
影响因子：
3.7
作者：
Regan, John F.;Kamitaki, Nolan;McCarroll, Steven A.
通讯作者：
McCarroll, Steven A.