美国密歇根大学医学院Sriram Venneti研究小组，揭示了在扩散型内因性脑桥神经胶质瘤（DIPG）中H3K27M突变引起的代谢和表观基因组重编程。该项研究成果在线发表在2020年8月13日的《癌细胞》上。

研究人员发现H3K27M和异柠檬酸脱氢酶1（IDH1）突变是互斥的，并且在实验上具有合成致命性。总体而言，研究人员证明了H3.3K27M和mIDH1以相反的方式劫持了一个保守且关键的代谢途径，以维持其优选的表观遗传状态。因此，阻断这种代谢/表观遗传途径在临床前模型中显示出有效的治疗效果，这揭示了许多急需治疗的关键靶点。

研究人员表示，H3K27M在DIPGs患者中是致命的并且缺乏有效的治疗方法。它们主要携带H3.3K27M突变，导致H3K27me3减少。对H3.3K27M细胞、肿瘤和患者体内成像的综合分析表明，糖酵解、谷氨酰胺分解和三羧酸循环代谢增强，α-酮戊二酸（α-KG）产量高。葡萄糖和/或谷氨酰胺衍生的α-KG在H3.3K27M细胞中维持较低的H3K27me3，抑制糖酵解或谷氨酰胺分解过程中的关键酶增加了H3K27me3、改变了染色质的可及性并延长了动物模型的存活时间。先前的研究表明，异柠檬酸脱氢酶（mIDH）1/2突变的胶质瘤细胞将α-KG转化为D-2-羟基戊二酸（D-2HG）以增加H3K27me3。

附：英文原文

Title: Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas

Author: Chan Chung, Stefan R. Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee, Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian K. Werner, Daniel R. Wahl, Costas A. Lyssiotis, Zhiguo Bian, J. Brad Shotwell, Viveka Nand Yadav, Carl Koschmann, Arul M. Chinnaiyan, Stefan Blüml, Alexander R. Judkins, Sriram Venneti

Issue&Volume: 2020-08-13

Abstract: H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. Theymainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysisin H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylicacid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/orglutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition ofkey enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatinaccessibility, and prolonged survival in animal models. Previous studies have shownthat mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate(D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutuallyexclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27Mand mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintaintheir preferred epigenetic state. Consequently, interruption of this metabolic/epigeneticpathway showed potent efficacy in preclinical models, suggesting key therapeutic targetsfor much needed treatments.

DOI: 10.1016/j.ccell.2020.07.008

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30369-X