IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response
IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response
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DOI：
10.1126/scitranslmed.aaq1427
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发表时间：
2019-02-13
影响因子：
17.1
通讯作者：
Castro, Maria G.
中科院分区：
文献类型：
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作者：
Nunez, Felipe J.;Mendez, Flor M.;Castro, Maria G.
肿瘤携带异柠檬酸脱氢酶1（IDH 1（R132 H））突变的胶质瘤患者在诊断时更年轻，寿命更长。IDH 1突变与其他分子病变共同发生，如1 p/19 q共缺失、肿瘤抑制蛋白53（TP 53）基因的失活突变和α地中海贫血/精神发育迟滞综合征X连锁基因（ATRX）的功能丧失突变。所有携带ATRX缺失的成人低级别胶质瘤（LGG）也表达IDH 1（R132 H）突变。目前LGG的分子分类部分基于这些突变的分布。我们开发了一种含有IDH 1（R132 H）、TP 53和ATRX失活突变并激活NRAS G12 V的基因工程小鼠模型。以前，我们确定ATRX缺陷，在野生型IDH 1的背景下，诱导基因组不稳定性，损害非同源末端连接DNA修复，并增加对DNA损伤疗法的敏感性。在这项研究中，使用我们的小鼠模型和具有IDH 1突变的原发性患者来源的胶质瘤培养物，我们研究了IDH 1（R132 H）在TP 53和ATRX丢失的背景下的功能。我们发现在ATRX和TP 53基因失活的遗传背景下IDH 1（R132 H）表达（i）在没有治疗的情况下增加中位生存期，（ii）通过共济失调-毛细血管扩张突变（ATM）信号通路的表观遗传上调增强DNA损伤反应（DDR），和（iii）增强肿瘤放射抗性。因此，药物抑制ATM或检查点激酶1和2，DDR中的必需激酶，恢复了肿瘤的放射敏感性。将这些发现转化为具有TP 53和ATRX丢失的IDH 1（132 H）胶质瘤患者可以提高放射治疗的疗效，从而提高患者的生存率。
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1(R132H)) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1(R132H) mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1(R132H), TP53 and ATRX inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1(R132H) in the context of TP53 and ATRX loss. We discovered that IDH1(R132H) expression in the genetic context of ATRX and TP53 gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1(132H) glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.