摘要

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.

译文

Bruton 酪氨酸激酶 (BTK) 将 b细胞抗原受体 (BCR) 和 Toll 样受体与 NF-κ B 联系起来。BTK 在原发性中枢神经系统 (CNS) 淋巴瘤 (PCNSL) 中的作用尚不清楚。我们用一流的 BTK 抑制剂伊布替尼对复发或难治性 CNS 淋巴瘤患者进行了 I 期临床试验。对伊布替尼的临床反应发生在 13 例 PCNSL 患者中的 10 例 (77%) 中,包括 5 例完全反应。唯一对伊布替尼完全耐药的 PCNSL 在已知的伊布替尼耐药机制 CARD11 的螺旋结构域内有突变。不完全肿瘤反应与 b细胞抗原受体相关蛋白 CD79B 的突变相关。CD79B-mutant PCNSLs 显示哺乳动物雷帕霉素靶蛋白 (mTOR) 相关基因集的富集,以及 PI3K/mTOR 激活标记的染色增加。抑制 PI3K 亚型 p110 α/p110 δ 或 mTOR 协同 ibrutinib 在 CD79B-mutant PCNSL 细胞中诱导细胞死亡。意义: 伊布替尼在复发或难治的 CNS b细胞淋巴瘤患者中具有大量活性。PCNSL 的反应率大大高于 CNS 外弥漫性大 b细胞淋巴瘤的报道,表明了不同的分子发病机制。BTK 和 PI3K/mTOR 的联合抑制可能会增加 CD79B-mutant 的人 PCNSLs 中的 ibrutinib 反应。癌症迪斯科; 7 (9); 1018-29。©2017 AACR。见 Lakshmanan 和 Byrd 的相关评论,940 页。这篇文章在本期专题 920 页中被强调。

bruton tyrosine kinase

肿瘤 慢性淋巴细胞性白血病 临床研究术语
概述  :  

布鲁顿酪氨酸激酶(BTK),即非受体酪氨酸激酶Tec家族的一个成员,是在除了T淋巴细胞和自然杀伤细胞之外的所有造血细胞类型中表达的关键信号酶。BTK在将细胞表面B细胞受体(BCR)刺激连接到下游细胞内应答的B细胞信号途径中发挥至关重要的作用。BTK是B细胞发育、激活、信号传导和存活的关键调节剂;另外,BTK在众多其它造血细胞信号途径中起作用,例如,巨噬细胞中Toll样受体(TLR)和细胞因子受体介导的TNF-α产生,肥大细胞中IgE受体(FceRI)的信号传导,B系淋巴样细胞中Fas/ΑΡ0

Bruton

释    义   n. (Bruton)人名;(英)布鲁顿;(法)布吕东

例    句   That year, I was giving the traditional Irish greeting, cad mle filte, a hundred thousand welcomes, to a new Irish prime minister, John Bruton, who was continuing the peace policy of his predecessor. 那一年,我给新任爱尔兰首相约翰.布鲁顿发出了“十万声欢迎”的爱尔兰传统祝福语,他正继续执行着前任的和平政策。

 

Tyrosine   英 /'taɪrəsiːn/   美 /'taɪrəsɪn/

释    义   n. [生化] 酪氨酸

例    句   Experts can not eat anything for depression, the problem was first set out the tyrosine content of foods and beverages, such as Chen cheese, canned meat, soy sauce, yeast extract, herring and salmon. 专家对于抑郁症不能吃什么这一问题首先罗列出了酪氨酸含量高的食物和饮料,如陈乳酪,罐头肉,酱油,酵母提取物,鲱鱼和鲑鱼等。

 

Kinase   英 /ˈkaɪneɪz/   美 /ˈkɪnneɪz/

释    义   n. [生化] 激酶;致活酶

例    句   However, the involvement of tyrosine kinase either directly or through the prostaglandins and nitric oxide synthase in response to inflammation during diabetes is not completely understood.不过,酪氨酸激酶是直接参与还是通过前列腺素和一氧化氮合酶对糖尿病炎症产生反应的,我们目前还不清楚。

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