Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma.
Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma.
复制标题
DOI：
10.1158/0008-5472.can-17-2269
复制
发表时间：
2018-06-01
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
在没有TERT的情况下，一组肿瘤使用基于重组的替代延长端粒(ALT)途径来解决端粒功能障碍。染色质重塑因子ATRX的功能缺失突变与ALT有关，但不足以推动这一过程。由于许多ALT肿瘤表达突变的异柠檬酸脱氢酶IDH1 R132H，包括所有低级别星形细胞瘤和继发性胶质母细胞瘤，我们研究了IDH1 R132H在胶质瘤形成过程中驱动ALT表型的假设作用。在p53/pRB缺陷型人星形胶质细胞中，ATRX基因的缺失和突变IDH1的表达足以产生具有ALT特征的肿瘤细胞。在这些致瘤细胞中，端粒封顶复合体成分RAP1和非同源DNA末端连接修复因子XRCC1均持续下调，它们的协同表达足以抑制ALT表型。RAP1或XRCC1下调与ATRX缺失协同驱动ALT表型。RAP1沉默导致ATRX缺陷细胞的端粒功能障碍，而XRCC1沉默通过允许IDH1突变的ATRX缺陷细胞使用同源重组和ALT来解决端粒功能障碍和逃脱细胞死亡来抑制功能障碍的端粒的致死性融合。总体而言，我们的研究表明，突变的IDH1的表达如何启动端粒功能障碍，改变端粒的DNA修复途径偏好，与ATRX丢失合作，击败胶质瘤形成的关键障碍。研究表明，突变型IDH1的表达如何启动端粒功能障碍，改变端粒DNA修复途径的偏好，与ATRX丢失合作，打破胶质瘤形成的关键障碍，并为治疗低级别胶质瘤提供新的治疗方案。
A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb–deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis. Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas.