Enhancing demethylation-induced differentiation in IDH-mutant glioma.
Enhancing demethylation-induced differentiation in IDH-mutant glioma.
复制标题
增强 IDH 突变神经胶质瘤的去甲基化诱导分化。
DOI：
10.1093/neuonc/noac056
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发表时间：
2022
期刊：
影响因子：
15.9
通讯作者：
Arrillaga-Romany,Isabel
中科院分区：
文献类型：
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作者：
Miller,JulieJ;Cahill,DanielP;Arrillaga-Romany,Isabel
由突变IDH 1或IDH 2酶产生的D-2-羟基戊二酸（2 HG）水平升高已被证明在建立神经胶质瘤CpG岛甲基化表型（G-CIMP）中起作用，其特征在于致病性全局超甲基化。1-3作为一种癌代谢物，2 HG抑制多种α-酮戊二酸依赖性双加氧酶，其中一个亚类通常作为DNA和组蛋白脱甲基酶发挥作用。2 HG诱导的表观遗传景观的变化有助于胶质瘤的发生，破坏典型的基因调控模式，导致胶质瘤干细胞程序的分化和异常维持受损。尽管在理解IDH突变型胶质瘤发展方面取得了这些实质性进展，但在开发有效的IDH突变型特异性疗法方面的进展仍然有限，去甲基化剂5-氮杂胞苷（5-aza）和地西他滨（DAC）是DNA甲基转移酶1（DNMT 1）抑制剂，正在研究用于治疗IDH-1。突变型神经胶质瘤这两种药物在IDH突变型胶质瘤异种移植模型中均表现出减缓肿瘤生长和延长存活的功效。4-6在本期《神经肿瘤学》杂志中，da Costa Rosa等人现在展示了这种方法的有效性，其中加入了促分化剂全反式维甲酸（atRA），这是一种临床上用于促进急性早幼粒细胞白血病（APL）治疗中终末分化的药物。7研究人员观察到，许多维甲酸相关基因在IDH突变型肿瘤中高度甲基化，这种模式在5-aza治疗患者来源的IDH突变型胶质瘤细胞时逆转。基于这些发现，他们假设低甲基化剂可以通过重新激活甲基化/沉默的基因来增强对atRA的敏感性。根据这一概念，联合治疗导致视黄酸反应元件的激活，特别是在IDH突变的背景下，尽管在IDH野生型和IDH突变型细胞系中，5-aza和atRA治疗后，几个视黄酸相关基因上调。令人兴奋的是，当5-氮杂环丁烷和5-氮杂环丁烷一起使用时，
Elevated levels of D-2-hydroxyglutarate (2HG) produced by mutant IDH1 or IDH2 enzymes have been shown to have a role in establishing the glioma CpG island methylator phenotype (G-CIMP), characterized by pathogenic global hypermethylation. 1–3 As an oncometabolite, 2HG inhibits a wide array of α-ketoglutaratedependent dioxygenases, a subset of which normally function as DNA and histone demethylases. A 2HG-induced change in the epigenetic landscape contributes to gliomagenesis, with the disruption of typical modes of gene regulation causing an impairment to differentiation and aberrant maintenance of a glioma stem-cell program. Despite these substantial advances in understanding of IDH-mutant glioma development, the progress in developing effective, IDH-mutant-specific therapies remains limited, with the current standard of care continuing to be comprised of radiation therapy and chemotherapeutics.The demethylating agents 5-azacytidine (5-aza) and decitabine (DAC) are DNA methyltransferase 1 (DNMT1) inhibitors that are under investigation for the treatment of IDH-mutant glioma. Both agents have demonstrated efficacy in slowing tumor growth and prolonging survival in IDH-mutant glioma xenograft models. 4–6 In this issue of Neuro-Oncology, da Costa Rosa et al now show enhanced effectiveness of this approach with the addition of prodifferentiation agent all-trans retinoic acid (atRA), an agent that is used clinically to promote terminal differentiation in the treatment of acute promyelocytic leukemia (APL). 7 The investigators observed that many retinoic acid-related genes are hypermethylated in IDH-mutant tumors, a pattern that was reversed with 5-aza treatment to patient-derived IDH-mutant glioma cells. Based on these findings, they postulate that a hypomethylating agent may enhance sensitivity to atRA by reactivating the methylated/silenced genes. In line with this concept, combination treatment led to activation of retinoic acid response elements specifically in the context of the IDH mutation, though several retinoic acid-related genes were upregulated upon both 5-aza and atRA treatment in both IDH-wildtype and IDH-mutant cell lines. Excitingly, when administered together, the combination of 5-aza