摘要

Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma and can be divided into 2 major molecular subtypes: the germinal center B-cell-like and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic B-cell receptor signaling and increased NF-κB activation contribute to ABC DLBCL survival. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation is independent of B-cell receptor signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT is activated in both DLBCL subtypes, long-term calcineurin inhibition with cyclosporin A or FK506, both clinically approved drugs, triggers potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors are associated with the reduced expression of c-Jun, interleukin-6, and interleukin-10, which were identified as NFAT target genes that are particularly important for the survival of ABC DLBCL. Furthermore, calcineurin blockade synergized with BCL-2 and MCL-1 inhibitors in killing ABC DLBCL cells. Collectively, these findings identify constitutive NFAT signaling as a crucial functional driver of ABC DLBCL and highlight calcineurin inhibition as a novel strategy for the treatment of this aggressive lymphoma subtype.

译文

弥漫大 b细胞淋巴瘤 (DLBCL) 是最常见的成人淋巴瘤,可分为 2 种主要的分子亚型: 生发中心 b细胞样和侵袭性活化 b细胞样 (ABC) DLBCL。先前的研究表明,慢性 b细胞受体信号和 NF-κ B 活化增加有助于 ABC DLBCL 的生存。在这里,我们表明转录因子 NFAT 的活性在两个 DLBCL 亚型中慢性升高。令人惊讶的是,NFAT 激活独立于 b细胞受体信号,但由钙通量增加和钙调磷酸酶介导的 NFAT 去磷酸化介导。有趣的是,尽管 NFAT 在两种 DLBCL 亚型中都被激活,但与环孢素a 或 FK506 一起的长期钙调神经磷酸酶抑制,这两种临床批准的药物,在 ABC DLBCL 细胞中特异性地触发了强有力的细胞毒性。钙调神经磷酸酶抑制剂的抗肿瘤作用与 c-6月、 interleukin-6 和 interleukin-10 的表达减少有关,它们被确定为对 ABC DLBCL 的生存特别重要的 NFAT 靶基因。此外,钙调神经磷酸酶阻断与 BCL-2 和 MCL-1 抑制剂协同杀死 ABC DLBCL 细胞。总的来说,这些发现确定组成性 NFAT 信号作为 ABC DLBCL 的关键功能驱动,并强调钙调磷酸酶抑制作为治疗这种侵袭性淋巴瘤亚型的新策略。

Diffuse Large B-Cell Lymphoma

消化 胃部常发肿瘤 疾病
概述  :  

弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)是一种具有高度异质性及侵袭性的B细胞淋巴瘤,在细胞遗传学、分子生物学、临床表现及疾病转归方面有明显异质性,是B细胞非霍奇金淋巴瘤中最常见的亚型。据统计,弥漫性大B细胞淋巴瘤患者约占所有新诊断B细胞非霍奇金淋巴瘤患者的40%。 流行病学无论在发达国家还是发展中国家, DLBCL发病率在非霍奇金淋巴瘤中均为最高。发好于老年人, 中位年龄为70岁, 也可见于儿童和青年, 男性略高于女性。患者可以

diffuse  英 [dɪˈfju:s] 美 [dɪˈfju:z]

释义   adj. 弥漫的;散开的

vt. 扩散;传播;漫射

例句   The change of photosensitizer diffuse characteristic have a great effect on the producing of singlet oxygen in epidermis and dermis, but no use in vessel. 光敏剂扩散特性的改变,对真皮和表皮中单线态氧的产生有较大影响,对血管中单线态氧的产生没有影响。

 

large 英 [lɑ:dʒ] 美 [lɑ:rdʒ]

释义   adj. 大的;多数的;广博的

adv. 大大地;夸大地

例句   Governance is not only for large organizations. 治理不仅是面向大型组织的。

 

cell 英 [sel] 美 [sel]

释义   n. 细胞;电池;蜂房的巢室;单人小室

vi. 住在牢房或小室中

例句   However, only a fraction of them are used in each cell. 但是,每一个细胞只用它们中的一小部分。

 

lymphoma 英 [lɪmˈfəʊmə] 美 [lɪmˈfoʊmə]

释义   n. [肿瘤] 淋巴瘤      复数 lymphomas或lymphomata

例句   Methods:To apply the position plate for position and set-up during the Lymphoma irradiation, and compare the effects with the traditional method. 方法:以恶性淋巴瘤为例,放疗过程中应用定位模板进行定位、复位、摆位,同时和传统的方法进行比较。


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