Low NUDT15 expression levels due to biallelic NUDT15 variants and 6-mercaptopurine intolerance.
Low NUDT15 expression levels due to biallelic NUDT15 variants and 6-mercaptopurine intolerance.
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DOI：
10.1111/bjh.18375
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发表时间：
2022-10
影响因子：
6.5
通讯作者：
中科院分区：
文献类型：
--
作者：
6-巯基嘌呤(6-MP)被广泛用于儿童白血病和淋巴瘤的治疗。最近，NUDT15基因的种系变异已被确认为6-MP相关不良反应(如骨髓抑制)的主要遗传原因之一。NUDT15亚型变异的患者在白细胞中积累了过量的DNA结合的硫鸟嘌呤，导致严重的骨髓抑制。尽管临床前研究表明这些变异可能会影响NUDT15的蛋白质稳定性，但这还没有直接在患者身上表现出来。在这项研究中，我们报道了一系列新的抗NUDT15的单抗的研制，并用夹心ELISA法定量检测了37例急性淋巴细胞白血病患者接受6-MP治疗后的NUDT15蛋白水平。NUDT15型与其蛋白水平高度相关(p<；0.0001)，纯合子和复合杂合子患者表现出极低的NUDT15表达。NUDT15蛋白水平与6-MP耐受性呈正相关(r=0.631，p<；0.0001)。总之，我们的结果指出，NUDT15蛋白丰度低是NUDT15介导的6-MP不耐受的生化基础，从而提供了遗传NUDT15缺陷的表型读数。
6-Mercaptopurine (6-MP) is widely used for the treatment of pediatric leukemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP–associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterized in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukemia treated with 6-MP, using Sandwich ELISA. The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.
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影响因子：
11.4
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
通讯作者：
Kato M
影响因子：
5.3
作者：
Somazu S;Tanaka Y;Tamai M;Watanabe A;Kagami K;Abe M;Harama D;Shinohara T;Akahane K;Goi K;Sugita K;Moriyama T;Yang J;Goto H;Minegishi M;Iwamoto S;Takita J;Inukai T
通讯作者：
Inukai T
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.
DOI：
10.1586/17474124.2015.1039987
发表时间：
2015-07-01
影响因子：
3.9
作者：
Goldberg, Rimma;Irving, Peter M.
通讯作者：
Irving, Peter M.
影响因子：
45.3
作者：
Yang, Jun J.;Landier, Wendy;Relling, Mary V.
通讯作者：
Relling, Mary V.