Heterozygous isocitrate dehydrogenase (IDH) R132H mutation (IDH1R132H/WT) is an early event during gliomagenesis. Clinically, patients with glioma carrying mutant IDH1 respond better to antitumor therapies. However, the mechanism by which IDH1 mutations contribute to gliomagenesis and therapeutic response remains elusive. Here we report that senescence is involved in the improved therapeutic responses of mutant IDH1 glioma cells. Knocking-in IDH1R132H/WT in glioma cells significantly enhanced gliomas cell senescence in response to temozolomide and radiation via a DNA-damage mediated mechanism. We further asked if senescence plays a role in IDH1R132H/WT-induced gliomagenesis. Together with ATRX knockout and p53/RB loss, IDH1R132H/WT transformed nonneoplastic human astroglial cells to form tumors in mouse brains. In-depth characterization revealed that a subset of these precancerous cells underwent senescence-like phenotypic changes, including flat and enlarged-cell morphology, increased senescence marker expression, decreased cell proliferation, and cell-cycle arrest at the G2–M phase. Mechanistic studies indicated that the combination of glioma driver genes (p53/RB/IDH1/ATRX) dramatically increased DNA damage and activated DNAdamage response (DDR) pathways ATR/ATR and Chk1/Chk2 in senescent cells. To determine how senescent cells drive tumor formation, we investigated non–cell-autonomous mechanisms such as senescence-associated secretory phenotype (SASP), a panel of proinflammatory and tissue-remodeling factors implicated in a tumor-permissive microenvironment. We found that astroglial cells carrying p53/RB/ATRX loss and IDH1R132H/WT upregulated key factors in SASP via an epigenetic-mediated mechanism. Our work suggests that drugs that specifically eliminate senescent cells could help kill precancerous cells and senescent tumor cells following antitumor therapies. Implications: The mechanisms by which IDH1 mutations contribute to gliomagenesis and therapeutic responses remain incompletely characterized; this work reveals senescence as a novel mechanism of IDH-mutant–mediated biological impact and describes new therapeutic opportunities concerning IDH1-mutant gliomas. This article is featured in Highlights of This Issue, [p. 1793][1] [1]: /lookup/volpage/19/1793?iss=11

中文翻译：

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单等位基因 IDH1 R132H 突变通过诱导衰老介导胶质瘤细胞对抗癌治疗的反应

杂合异柠檬酸脱氢酶 (IDH) R132H 突变 (IDH1R132H/WT) 是胶质瘤发生过程中的早期事件。临床上，携带突变 IDH1 的胶质瘤患者对抗肿瘤治疗反应更好。然而，IDH1 突变导致胶质瘤发生和治疗反应的机制仍然难以捉摸。在这里，我们报告衰老与突变 IDH1 胶质瘤细胞的治疗反应改善有关。胶质瘤细胞中的敲入 IDH1R132H/WT 通过 DNA 损伤介导的机制显着增强了胶质瘤细胞对替莫唑胺和辐射的反应。我们进一步询问衰老是否在 IDH1R132H/WT 诱导的胶质瘤发生中起作用。连同 ATRX 敲除和 p53/RB 丢失，IDH1R132H/WT 转化非肿瘤性人星形胶质细胞，在小鼠大脑中形成肿瘤。深入表征显示，这些癌前细胞中的一部分经历了类似衰老的表型变化，包括扁平和增大的细胞形态、衰老标志物表达增加、细胞增殖减少和 G2-M 期细胞周期停滞。机制研究表明，胶质瘤驱动基因 (p53/RB/IDH1/ATRX) 的组合显着增加了衰老细胞中的 DNA 损伤和激活的 DNA 损伤反应 (DDR) 通路 ATR/ATR 和 Chk1/Chk2。为了确定衰老细胞如何驱动肿瘤形成，我们研究了非细胞自主机制，例如衰老相关分泌表型 (SASP)，这是一组与肿瘤允许微环境有关的促炎和组织重塑因子。我们发现携带 p53/RB/ATRX 缺失和 IDH1R132H/WT 的星形胶质细胞通过表观遗传介导的机制上调 SASP 中的关键因子。我们的工作表明，特异性消除衰老细胞的药物可以帮助在抗肿瘤治疗后杀死癌前细胞和衰老的肿瘤细胞。启示：IDH1 突变导致胶质瘤发生和治疗反应的机制仍未完全确定；这项工作揭示了衰老是 IDH 突变体介导的生物学影响的一种新机制，并描述了有关 IDH1 突变体神经胶质瘤的新治疗机会。这篇文章被收录在本期的亮点中，[p. 1793][1][1]：/lookup/volpage/19/1793?iss=11 我们的工作表明，特异性消除衰老细胞的药物可以帮助在抗肿瘤治疗后杀死癌前细胞和衰老的肿瘤细胞。启示：IDH1 突变导致胶质瘤发生和治疗反应的机制仍未完全确定；这项工作揭示了衰老是 IDH 突变体介导的生物学影响的一种新机制，并描述了有关 IDH1 突变体神经胶质瘤的新治疗机会。这篇文章被收录在本期的亮点中，[p. 1793][1][1]：/lookup/volpage/19/1793?iss=11 我们的工作表明，特异性消除衰老细胞的药物可以帮助在抗肿瘤治疗后杀死癌前细胞和衰老的肿瘤细胞。启示：IDH1 突变导致胶质瘤发生和治疗反应的机制仍未完全确定；这项工作揭示了衰老是 IDH 突变体介导的生物学影响的一种新机制，并描述了有关 IDH1 突变体神经胶质瘤的新治疗机会。这篇文章被收录在本期的亮点中，[p. 1793][1][1]：/lookup/volpage/19/1793?iss=11 这项工作揭示了衰老是 IDH 突变体介导的生物学影响的一种新机制，并描述了有关 IDH1 突变体神经胶质瘤的新治疗机会。这篇文章被收录在本期的亮点中，[p. 1793][1][1]：/lookup/volpage/19/1793?iss=11 这项工作揭示了衰老是 IDH 突变体介导的生物学影响的一种新机制，并描述了有关 IDH1 突变体神经胶质瘤的新治疗机会。这篇文章被收录在本期的亮点中，[p. 1793][1][1]：/lookup/volpage/19/1793?iss=11