NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells.
NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells.
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DOI：
10.1111/jcmm.16981
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Inukai T
中科院分区：
文献类型：
--
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
在儿童急性淋巴细胞白血病（ALL）的化疗中，每日口服巯基嘌呤和每周甲氨蝶呤组成的维持治疗是重要的。据报道，NUDT 15变异基因型与维持治疗期间的重度骨髓抑制高度相关，特别是在亚洲和西班牙裔人群中。研究还表明，在一部分复发性儿童ALL中可检测到参与硫嘌呤代谢的NT 5C 2和PRPS 1基因的获得性体细胞突变。为了直接证实NUDT 15变异基因型和NT 5C 2和PRPS 1突变在白血病细胞内在基因中的硫嘌呤敏感性中的意义，我们研究了84个B-细胞前体-ALL（BCP-ALL）细胞系。3个和14个细胞系分别具有NUDT 15基因的纯合和杂合变体双倍型，而仅从复发时的样品建立的4个和2个细胞系分别具有NT 5C 2和PRPS 1突变。暴露于治疗浓度的硫鸟嘌呤后，NUDT 15变体基因型以及NT 5C 2和PRPS 1突变均与DNA掺入的硫鸟嘌呤水平显着相关。考虑到维持治疗期间的连续暴露，我们评价了暴露7天后的体外巯基嘌呤敏感性。对50%白血病细胞致死的巯基嘌呤浓度与巯基嘌呤的治疗血清浓度相当。NUDT 15变异基因型以及NT 5C 2和PRPS 1突变与83个BCP-ALL和23个T-ALL细胞系中的巯基嘌呤敏感性显著相关。本研究提供了直接的证据来支持的一般原则，表明遗传基因型和体细胞获得性突变是至关重要的白血病细胞的药物敏感性。
In chemotherapy for childhood acute lymphoblastic leukaemia (ALL), maintenance therapy consisting of oral daily mercaptopurine and weekly methotrexate is important. NUDT15 variant genotype is reportedly highly associated with severe myelosuppression during maintenance therapy, particularly in Asian and Hispanic populations. It has also been demonstrated that acquired somatic mutations of the NT5C2 and PRPS1 genes, which are involved in thiopurine metabolism, are detectable in a portion of relapsed childhood ALL. To directly confirm the significance of the NUDT15 variant genotype and NT5C2 and PRPS1 mutations in thiopurine sensitivity of leukaemia cells in the intrinsic genes, we investigated 84 B‐cell precursor‐ALL (BCP‐ALL) cell lines. Three and 14 cell lines had homozygous and heterozygous variant diplotypes of the NUDT15 gene, respectively, while 4 and 2 cell lines that were exclusively established from the samples at relapse had the NT5C2 and PRPS1 mutations, respectively. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with DNA‐incorporated thioguanine levels after exposure to thioguanine at therapeutic concentration. Considering the continuous exposure during the maintenance therapy, we evaluated in vitro mercaptopurine sensitivity after 7‐day exposure. Mercaptopurine concentrations lethal to 50% of the leukaemia cells were comparable to therapeutic serum concentration of mercaptopurine. Both NUDT15 variant genotype and NT5C2 and PRPS1 mutations were significantly associated with mercaptopurine sensitivity in 83 BCP‐ALL and 23 T‐ALL cell lines. The present study provides direct evidence to support the general principle showing that both inherited genotype and somatically acquired mutation are crucially implicated in the drug sensitivity of leukaemia cells.
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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：
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：
6.5
作者：
Kang, J;Kisenge, RR;Komada, Y
通讯作者：
Komada, Y
影响因子：
20.3
作者：
Balis，FM;Holcenberg，JS;Bleyer，WA
通讯作者：
Bleyer，WA
影响因子：
3.5
作者：
Kodidela, Sunitha;Dorababu, Patchava;Uppugunduri, Chakradhara Rao Satyanarayana
通讯作者：
Uppugunduri, Chakradhara Rao Satyanarayana