LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates
LMP1 mediates multinuclearity through downregulation of shelterin proteins and formation of telomeric aggregates
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DOI：
10.1182/blood-2014-08-594176
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发表时间：
2015-03-26
期刊：
影响因子：
20.3
通讯作者：
Knecht, Hans
中科院分区：
文献类型：
--
作者：
Lajoie, Valerie;Lemieux, Bruno;Knecht, Hans
霍奇金淋巴瘤（HL）和伯基特淋巴瘤都是生发中心来源的B细胞淋巴瘤。为了评估在EB病毒（EBV）相关HL肿瘤细胞中观察到的永久性潜伏膜蛋白1（LMP 1）表达的后果，我们分析了三维（3D）端粒动力学，并在转录和翻译水平上测量了shelterin蛋白的表达及其在EBV阴性Burkitt细胞系BJAB中的地形分布，该细胞系稳定转染了诱导型LMP 1系统。与LMP 1抑制的BJAB对照相比，稳定的LMP 1表达导致多核细胞、核体积和3D端粒聚集体的高度显著增加。最重要的是，LMP 1诱导了shelterin组分TRF 1，TRF 2和POT 1在转录和翻译水平上的显著下调，并且这种下调在LMP 1的再抑制后被逆转。此外，如光谱核型分析所揭示的，LMP 1诱导了“外”巨细胞和亚倍体“鬼”细胞。这种LMP 1诱导的多核化在LMP 1非依赖性TRF 2表达后被阻断。这些结果表明，LMP 1依赖的端粒稳定性和核组织的失调，通过shelterin下调，特别是TRF 2，有利于染色体重排。我们推测端粒聚集体和正在进行的断裂-桥-融合周期导致胞质分裂紊乱，最终导致多核性，如在EBV相关HL中观察到的。
Hodgkin lymphoma (HL) and Burkitt lymphoma are both germinal center-derived B-cell lymphomas. To assess the consequences of permanent latent membrane protein 1 (LMP1) expression as observed in tumor cells of Epstein-Barr virus (EBV) -associated HL, we analyzed 3-dimensional (3D) telomere dynamics and measured the expression of shelterin proteins at the transcriptional and translational level and their topographic distribution in the EBV-negative Burkitt cell line BJAB stably transfected with an inducible LMP1 system. Stable LMP1 expression led to a highly significant increase of multinucleated cells, nuclear volume, and 3D telomeric aggregates when compared with the LMP1-suppressed BJAB controls. Most importantly, LMP1 induced a significant down-regulation of the shelterin components TRF1, TRF2, and POT1 at the transcriptional and translational level, and this downregulation was reversed after resuppression of LMP1. In addition, as revealed by spectral karyotyping, LMP1 induced "outre" giant cells and hypoploid "ghost" cells. This LMP1-induced multinucleation was blocked upon LMP1-independent TRF2 expression. These results show that LMP1-dependent deregulation of telomere stability and nuclear organization via shelterin downregulation, in particular TRF2, favors chromosomal rearrangements. We speculate that telomeric aggregates and ongoing breakage-bridge-fusion cycles lead to disturbed cytokinesis and finally to multinuclearity, as observed in EBV-associated HL.