Faumont Nathalie, Chanut Aurélie, Benard Alan, Cogne Nadine, Delsol Georges, Feuillard Jean, Meggetto Fabienne
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Haematologica. 2009 Mar;94(3):355-63. doi: 10.3324/haematol.13269. Epub 2009 Feb 11.
In Epstein-Barr virus-associated Hodgkin's lymphomas, neoplastic Reed-Sternberg cells and surrounding non-tumor B-cells contain different variants of the LMP1-BNLF1 oncogene. In this study, we raised the question of functional properties of latent membrane protein 1 (LMP1) natural variants from both Reed-Sternberg and non-tumor B-cells.
Twelve LMP1 natural variants from Reed-Sternberg cells, non-tumor B-cells of Hodgkin's lymphomas and from B-cells of benign reactive lymph nodes were cloned, sequenced and stably transfected in murine recombinant interleukin-3-dependent Ba/F3 cells to search for relationships between LMP1 cellular origin and oncogenic properties as well as nuclear factor-kappaB activation, and apoptosis protection.
LMP1 variants of Reed-Sternberg cell origin were often associated with increased mutation rate and with recurrent genetic events, such as del15bp associated with S to N replacement at codon 309, and four substitutions I85L, F106Y, I122L, and M129I. Oncogenic potential (growth factor-independence plus clonogenicity) was consistently associated with LMP1 variants from Reed-Sternberg cells, but inconstantly for LMP1-variants from non-tumor B-cells. Analysis of LMP1 variants from both normal B-cells and Reed-Sternberg cells indicates that protection against apoptosis through activation of nuclear factor-kappaB - whatever the cellular origin of LMP1 - was maintained intact, regardless of the mutational pattern.
Taken together, our results demonstrate that preserved nuclear factor-kappaB activity and protection against apoptosis would be the minimal prerequisites for all LMP1 natural variants from both normal and tumor cells in Hodgkin's lymphomas, and that oncogenic potential would constitute an additional feature for LMP1 natural variants in Reed-Sternberg cells.
在爱泼斯坦-巴尔病毒相关的霍奇金淋巴瘤中，肿瘤性里德-斯腾伯格细胞和周围的非肿瘤性B细胞含有LMP1-BNLF1癌基因的不同变体。在本研究中，我们提出了来自里德-斯腾伯格细胞和非肿瘤性B细胞的潜伏膜蛋白1（LMP1）天然变体的功能特性问题。
克隆、测序并将来自里德-斯腾伯格细胞、霍奇金淋巴瘤的非肿瘤性B细胞以及良性反应性淋巴结B细胞的12种LMP1天然变体稳定转染至小鼠重组白细胞介素-3依赖的Ba/F3细胞中，以寻找LMP1细胞来源与致癌特性以及核因子-κB激活和凋亡保护之间的关系。
里德-斯腾伯格细胞来源的LMP1变体通常与突变率增加和复发性遗传事件相关，如与密码子309处S到N替换相关的15bp缺失，以及四个替换I85L、F106Y、I122L和M129I。致癌潜力（生长因子非依赖性加克隆形成性）始终与里德-斯腾伯格细胞的LMP1变体相关，但与非肿瘤性B细胞的LMP1变体的相关性不稳定。对正常B细胞和里德-斯腾伯格细胞的LMP1变体分析表明，无论LMP1的细胞来源如何，通过激活核因子-κB来保护细胞免受凋亡的功能均保持完整，而与突变模式无关。
综上所述，我们的结果表明，保留核因子-κB活性和保护细胞免受凋亡是霍奇金淋巴瘤中正常细胞和肿瘤细胞所有LMP1天然变体的最低先决条件，而致癌潜力将是里德-斯腾伯格细胞中LMP1天然变体的一个额外特征。
