Fas gene mutation in the progression of adult T cell leukemia
Fas gene mutation in the progression of adult T cell leukemia
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DOI：
10.1084/jem.189.7.1063
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发表时间：
1999-04-05
影响因子：
15.3
通讯作者：
Kamihira, S
中科院分区：
文献类型：
--
作者：
Maeda, T;Yamada, Y;Kamihira, S
Fas 抗原 (Apo-1/CD95) 是一种凋亡信号细胞表面受体，属于肿瘤坏死因子受体超家族。成人 T 细胞白血病 (ATL) 细胞表达 Fas 抗原，并在用抗 Fas 单克隆抗体处理后显示细胞凋亡。我们建立了ATL细胞系KOB，该细胞系对Fas介导的细胞凋亡表现出抵抗力，并发现KOB表达两种形式的Fas mRNA，即正常形式和截短形式。截短的转录本在外显子 9 处缺少 20 个碱基对，导致移码并生成 a。氨基酸239处的提前终止密码子。在原代腹水细胞和外周血细胞中检测到相同的突变。然而，尽管所有原代 ATL 细胞都具有相同的克隆起源，但在淋巴结细胞中并未检测到该突变。逆转录病毒介导的截短 Fas 基因转移至 Jurkat 细胞，使细胞对 Fas 介导的细胞凋亡具有抵抗力，表明存在显性负干扰机制。这些结果表明，ATL亚克隆在淋巴结中获得了Fas突变，使得亚克隆能够逃避Fas/Fas配体系统介导的细胞凋亡并在体内增殖。 Fas基因突变可能是ATL进展的机制之一。
Fas antigen (Apo-1/CD95) is an apoptosis-signaling cell surface receptor belonging to the tumor necrosis factor receptor superfamily. Adult T cell leukemia (ATL) cells express Fas antigen and show apoptosis after treatment with an anti-Fas monoclonal antibody. We established the ATL cell line KOB, which showed resistance to Fas-mediated apoptosis, and found that KOB expressed two forms of Fas mRNA, the normal form and a truncated form. The truncated transcript lacked 20 base pairs at exon 9, resulting in a Frame shift and the generation of a. premature stop codon at amino acid 239. The same mutation was detected in primary ascitic cells and peripheral blood cells. The mutation was not detected in lymph node cells, however, although all of the primary ATL cells were of the same clonal origin. A retroviral-mediated gene transfer of the truncated Fas to Jurkat cells rendered the cells resistant to Fas-mediated apoptosis, suggesting a dominant negative interference mechanism. These results indicate that an ATL subclone acquires a Fas mutation in the lymph nodes, enabling the subclone to escape from apoptosis mediated by the Fas/Fas ligand system and proliferate in the body. Mutation of the Fas gene may be one of the mechanisms underlying the progression of ATL.