文章目录

idh突变型胶质瘤进展过程中细胞状态的进化和致癌驱动因素

原文发布日期：2024-11-21

英文摘要：

摘要翻译：

原文链接：

文章：

idh突变型胶质瘤进展过程中细胞状态的进化和致癌驱动因素

Evolving cell states and oncogenic drivers during the progression of IDH-mutant gliomas

原文发布日期：2024-11-21

英文摘要：

Isocitrate dehydrogenase (IDH) mutants define a class of gliomas that are initially slow-growing but inevitably progress to fatal disease. To characterize their malignant cell hierarchy, we profiled chromatin accessibility and gene expression across single cells from low-grade and high-grade IDH-mutant gliomas and ascertained their developmental states through a comparison to normal brain cells. We provide evidence that these tumors are initially fueled by slow-cycling oligodendrocyte progenitor cell-like cells. During progression, a more proliferative neural progenitor cell-like population expands, potentially through partial reprogramming of ‘permissive’ chromatin in progenitors. This transition is accompanied by a switch from methylation-based drivers to genetic ones. In low-grade IDH-mutant tumors or organoids, DNA hypermethylation appears to suppress interferon (IFN) signaling, which is induced by IDH or DNA methyltransferase 1 inhibitors. High-grade tumors frequently lose this hypermethylation and instead acquire genetic alterations that disrupt IFN and other tumor-suppressive programs. Our findings explain how these slow-growing tumors may progress to lethal malignancies and have implications for therapies that target their epigenetic underpinnings.

摘要翻译：

I类 IDH 突变体定义了一种特殊的胶质母细胞肿瘤，它们最初生长缓慢，但最终会发展为致命性疾病。为了表征这些恶性细胞的分层关系，我们从低级和高级 I 类 IDH突变体胶质母细胞肿瘤中进行了单细胞染色质可及性和基因表达分析，并通过与正常脑细胞的比较来确定它们的发展状态。我们提供证据表明，这类肿瘤最初是由慢循环的寡核苷酸前胶质母细胞类似物驱动的。在进展过程中，一个更具增殖性的神经元前体细胞类似群体扩张，这可能部分通过祖粒的“宽松”染色质重新编程实现。这种转变伴随着从基于甲基化的驱动因素向遗传驱动因素的转变。在低级 I 类 IDH突变体肿瘤或器官样组织中，DNA 超高染色出现抑制干扰素（IFN）信号的作用。高级肿瘤常失去这种超高染色，并且获得破坏 IFN 和其他肿瘤抑制程序的基因改变。我们的发现解释了这类缓慢生长的肿瘤如何发展为致命恶性肿瘤，并为靶向其表观遗传学基础的疗法提供了意义。