Knecht Hans, Mai Sabine
Division of Haematology, Department of Medicine, Jewish General Hospital, McGill University, Montréal, QC H3T 1E2, Canada.
Manitoba Institute of Cell Biology, The Genomic Centre for Cancer Research and Diagnosis, University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
Viruses. 2017 Jun 27;9(7):164. doi: 10.3390/v9070164.
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells in classical EBV-positive Hodgkin's lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In a conditional, germinal-center-derived B-cell in vitro system, LMP1 reversibly down-regulates the shelterin proteins, telomeric repeat binding factor (TRF)1, TRF2, and protection of telomeres (POT)1. This down-regulation is associated with progressive 3D shelterin disruption, resulting in telomere dysfunction, progression of complex chromosomal rearrangements, and multinuclearity. TRF2 appears to be the key player. Thus, we hypothesize that the 3D interaction of telomeres and TRF2 is disrupted in H cells, and directly associated with the formation of H and RS cells. Using quantitative 3D co-immuno-TRF2-telomere fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) applied to monolayers of primary H and RS cells, we demonstrate TRF2-telomere dysfunction in EBV-positive cHL. However, in EBV-negative cHL a second molecular mechanism characterized by massive up-regulation of TRF2, but attrition of telomere signals, is also identified. These facts point towards a shelterin-related pathogenesis of cHL, where two molecularly disparate mechanisms converge at the level of 3D Telomere-TRF2 interactions, leading to the formation of RS cells.
爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）在经典EBV阳性霍奇金淋巴瘤（cHL）生发中心来源的单核霍奇金（H）细胞以及多核诊断性里德-斯腾伯格（RS）细胞中表达。在EBV阴性的H细胞系中表达LMP1会导致RS细胞数量显著增加。在一个条件性生发中心来源的B细胞体外系统中，LMP1可逆性下调端粒保护蛋白，端粒重复序列结合因子（TRF）1、TRF2和端粒保护蛋白（POT）1。这种下调与渐进性的三维端粒保护蛋白破坏有关，导致端粒功能障碍、复杂染色体重排进展以及多核化。TRF2似乎是关键因素。因此，我们推测在H细胞中端粒与TRF2的三维相互作用被破坏，并且与H细胞和RS细胞的形成直接相关。通过对原发性H细胞和RS细胞单层应用定量三维共免疫TRF2-端粒荧光原位杂交（3D TRF2/Telo-Q-FISH），我们证明了EBV阳性cHL中存在TRF2-端粒功能障碍。然而，在EBV阴性cHL中还发现了另一种分子机制，其特征是TRF2大量上调，但端粒信号减弱。这些事实表明cHL存在一种与端粒保护蛋白相关的发病机制，其中两种分子机制不同的机制在三维端粒-TRF2相互作用水平上汇聚，导致RS细胞的形成。
