Association between mutant IDHs and tumorigenesis in gliomas.
Association between mutant IDHs and tumorigenesis in gliomas.
复制标题
突变 IDH 与神经胶质瘤肿瘤发生之间的关联。
DOI：
10.1007/s00795-018-0189-8
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Hirose Y
中科院分区：
文献类型：
--
作者：
Ohba S;Hirose Y
为了永生化，细胞需要通过端粒酶的激活或端粒的替代延长来维持端粒长度。 IDH1/2 突变与神经胶质瘤发生的早期阶段密切相关。先前的研究表明，突变 IDH1/2 诱导的 2-HG 积累会抑制 α-KG 依赖性脱氧酶，并导致全基因组组蛋白和 DNA 甲基化改变。这些改变被认为有助于肿瘤发生。 H-Ras可以通过p53/pRb失活和hTERT表达来转化人星形胶质细胞；然而，突变的 IDH1 也可以转化细胞。此外，突变体 IDH1 可以通过重新激活端粒酶和稳定端粒，结合增加组蛋白赖氨酸甲基化和 TERT 启动子上的 c-Myc/Max 结合来驱动 p53-/pRb 缺陷型星形胶质细胞的永生化和转化。目前尚不清楚突变的 IDH1/2 是否仅作为神经胶质瘤发生的初始驱动因素或维持转化的细胞。正在进行临床研究以评估突变 IDH1/2 抑制剂治疗神经胶质瘤的用途。
To become immortalized, cells need to maintain the telomere length via the activation of telomerase or alternative lengthening of telomere. Mutations inIDH1/2 are strongly associated with the early stage of gliomagenesis. Previous work has shown that the accumulation of 2-HG, which is induced by mutant IDH1/2, inhibits α-KG-dependent deoxygenase and leads to genome-wide histone and DNA methylation alterations. These alterations are believed to contribute to tumorigenesis. H-Ras can transform human astrocytes with the inactivation of p53/pRb and expression of hTERT; however, mutant IDH1 can also transform cells. Moreover, mutant IDH1 can drive the immortalization and transformation of p53-/pRb-deficient astrocytes by reactivating telomerase and stabilizing telomeres in combination with increased histone lysine methylation and c-Myc/Max binding at theTERTpromoter. It remains unclear whether mutant IDH1/2 acts only as the initial driver of gliomagenesis or it maintains transformed cells. Clinical studies are being performed to assess the use of mutant IDH1/2 inhibitors for treating gliomas.