Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.
Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.
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弥漫性内源性脑桥胶质瘤的转录依赖性
DOI：
10.1016/j.ccell.2017.03.011
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发表时间：
2017-05-08
期刊：
影响因子：
50.3
通讯作者：
Monje M
中科院分区：
文献类型：
--
作者：
Nagaraja S;Vitanza NA;Woo PJ;Taylor KR;Liu F;Zhang L;Li M;Meng W;Ponnuswami A;Sun W;Ma J;Hulleman E;Swigut T;Wysocka J;Tang Y;Monje M
弥漫性内在脑桥胶质瘤（DIPG）是一种致命的儿科癌症，治疗选择有限。大多数DIPG病例表现出组蛋白3（H3 K27 M）突变，导致致癌转录异常。我们在这里表明，DIPG是脆弱的转录破坏使用布罗莫结构域抑制或CDK7封锁。通过这些方法中的任一种靶向致癌转录与HDAC抑制协同作用，并且对HDAC抑制剂疗法具有抗性的DIPG细胞保持对CDK7阻断的敏感性。DIPG中超级增强子的鉴定提供了对起源细胞的见解，突出了少突胶质细胞谱系基因，并揭示了介导肿瘤活力和侵袭的意想不到的机制，包括钾通道功能和EPH受体信号传导。这些发现证明了转录的脆弱性，并阐明了以前未知的DIPG病理学机制。
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.