Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.,Cancer Cell

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Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.
Cancer Cell ( IF 50.3 ) Pub Date : 2020-08-13 , DOI: 10.1016/j.ccell.2020.07.008
Chan Chung ₁ , Stefan R Sweha ₂ , Drew Pratt ₁ , Benita Tamrazi ₃ , Pooja Panwalkar ₁ , Adam Banda ₁ , Jill Bayliss ₁ , Debra Hawes ₄ , Fusheng Yang ₄ , Ho-Joon Lee ₅ , Mengrou Shan ₅ , Marcin Cieslik ₆ , Tingting Qin ₇ , Christian K Werner ₈ , Daniel R Wahl ₈ , Costas A Lyssiotis ₅ , Zhiguo Bian ₉ , J Brad Shotwell ₉ , Viveka Nand Yadav ₁₀ , Carl Koschmann ₁₀ , Arul M Chinnaiyan ₆ , Stefan Blüml ₃ , Alexander R Judkins ₄ , Sriram Venneti ₁₁

Affiliation

Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Michigan Medicine, University of Michigan, 3520E MSRB 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-41804, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Michigan Medicine, University of Michigan, 3520E MSRB 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-41804, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Michigan Center for Translational Pathology, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Centralized Medicinal Chemistry, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Michigan Medicine, University of Michigan, 3520E MSRB 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-41804, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that 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 mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.

中文翻译：

通过 H3K27M 突变在弥漫性内源性脑桥胶质瘤中进行综合代谢和表观基因组重编程。

H3K27M 弥漫性内在性脑桥胶质瘤 (DIPG) 是致命的且缺乏治疗方法。它们主要包含 H3.3K27M 突变，导致 H3K27me3 减少。H3.3K27M 细胞、肿瘤和体内的综合分析患者的成像显示糖酵解、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 细胞中保持低 H3K27me3，抑制糖酵解或谷氨酰胺分解中的关键酶会增加 H3K27me3，改变染色质可及性，并延长动物模型的存活时间。先前的研究表明，突变异柠檬酸脱氢酶 (mIDH)1/2 神经胶质瘤细胞将 α-KG 转化为 D-2-羟基戊二酸 (D-2HG) 以增加 H3K27me3。在这里，我们表明 H3K27M 和 IDH1 突变是相互排斥的，并且通过实验合成致死。总体而言，我们证明 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，以维持其首选的表观遗传状态。最后，

更新日期：2020-09-14

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