Clinical significance of polyglutamylation in primary central nervous system lymphoma.
Clinical significance of polyglutamylation in primary central nervous system lymphoma.
复制标题
DOI：
10.1186/s40478-018-0522-4
复制
发表时间：
2018-02-23
影响因子：
7.1
通讯作者：
Mukasa A
中科院分区：
文献类型：
--
作者：
Shinojima N;Fujimoto K;Makino K;Todaka K;Yamada K;Mikami Y;Oda K;Nakamura K;Jono H;Kuratsu JI;Nakamura H;Yano S;Mukasa A
原发性中枢神经系统淋巴瘤（PCNSL）对大剂量甲氨蝶呤（HD-MTX）治疗的反应各不相同。多聚谷氨酰化是一种可逆的蛋白质修饰，在肿瘤细胞中发生率很高。MTX掺入细胞是多聚谷氨酰化的，并强烈结合二氢叶酸还原酶，而不受亚叶酸（LV）的竞争性抑制。具有高聚谷氨酰化水平的肿瘤细胞被选择性地杀死，而具有较低聚谷氨酰化水平的正常细胞被LV拯救。我们假设肿瘤细胞中多聚谷氨酰化的程度决定了治疗耐药性。在此，我们基于多聚谷氨酰化状态研究了PCNSL对HD-MTX治疗和LV补救的治疗反应。在2001年至2014年期间在我科接受HD-MTX治疗的113例连续PCNSL患者中，通过免疫染色对82例患者的多聚谷氨酰胺化进行了评估，并回顾性检查了多聚谷氨酰胺化与治疗反应之间的关系。利用人恶性淋巴瘤细胞系进行体外实验，用短发夹RNA敲低诱导多聚谷氨酰化的folpolyglutamate synthetase（FPGS），建立了具有低多聚谷氨酰化速率的稳定细胞系。使用丁酸钠（NaBu）评价MTX治疗LV挽救后的细胞活力，丁酸钠是一种组蛋白脱乙酰酶抑制剂，通过升高FPGS表达诱导聚谷氨酰胺化。多聚谷氨酰化组的完全缓解率显著高于非多聚谷氨酰化组[分别为58.1%（25/43）和33.3%（13/39）]（p < 0.05），多聚谷氨酰化组的无进展生存期也显著增加（p < 0.01）。在体外，MTX给药后LV的缓解作用在al细胞系中FPGS敲低后显著增强，而NaBu治疗的FPGS表达增强显著降低了这种缓解作用。这些结果表明，多聚谷氨酰胺化可能是PCNSL患者对HD-MTX治疗伴LV挽救治疗的治疗反应的预测因子。HD-MTX和多聚谷氨酰化诱导剂的联合治疗可能是PCNSL治疗的一种有前途的策略。
The therapeutic response to high-dose methotrexate (HD-MTX) therapy for primary central nervous system lymphoma (PCNSL) varies. Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. MTX incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. We hypothesized that the extent of polyglutamylation in tumor cells determines treatment resistance. Here, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status. Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma lines were used for in vitro experiments, and folpolyglutamate synthetase (FPGS), which induces polyglutamylation, was knocked down with short-hairpin RNA, and a stable cell line with a low rate of polyglutamylation was established. Cell viability after MTX treatment with LV rescue was evaluated using sodium butyrate (NaBu), a histone-deacetylase inhibitor that induces polyglutamylation by elevating FPGS expression. The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (p < 0.05), and progression-free survival was also significantly increased in the group with polyglutamylation (p < 0.01). In vitro, the relief effect of LV after MTX administration was significantly enhanced after FPGS knockdown in al cell lines, whereas enhancement of FPGS expression by NaBu treatment significantly reduced this relief effect. These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combination therapy with HD-MTX and polyglutamylation-inducing agents might represent a promising strategy for PCNSL treatment.
登录
查看更多内容
影响因子：
11.2
作者：
Shinojima N;Hossain A;Takezaki T;Fueyo J;Gumin J;Gao F;Nwajei F;Marini FC;Andreeff M;Kuratsu J;Lang FF
通讯作者：
Lang FF
影响因子：
3.4
作者：
Joerger, Markus;Ferreri, Andres J. M.;Huitema, Alwin D. R.
通讯作者：
Huitema, Alwin D. R.
DOI：
10.1016/j.ijrobp.2005.07.958
发表时间：
2006-02-01
影响因子：
7
作者：
O'Brien, PC;Roos, DE;Trotter, GE
通讯作者：
Trotter, GE
影响因子：
13.3
作者：
Aoki, Hiroshi;Kondo, Yasuko;Kondo, Seiji
通讯作者：
Kondo, Seiji
影响因子：
17.1
作者：
Mlecnik, Bernhard;Bindea, Gabriela;Galon, Jerome
通讯作者：
Galon, Jerome