耶鲁医学院Roel G. W. Verhaak小组近日取得一项新成果。经过不懈努力，他们的最新研究提出了IDH突变型胶质瘤进展中的获得性遗传和细胞状态改变。相关论文于2026年6月3日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该团队整合了来自35例患者的75例暂时分离的胶质瘤的单核转录组谱、染色质可及性谱和大量DNA和RNA测序，这些患者包括少突胶质细胞瘤和星形细胞瘤IDH突变型胶质瘤。研究小组发现，恶性细胞状态在转录上类似于正常胶质-神经元谱系发育阶段或反应性间充质样状态，反映了先前在IDH野生型胶质母细胞瘤中描述的状态。恶性细胞状态显示出不同的染色质可及性特征，在两种IDH突变胶质瘤类型之间具有可比性。低分化恶性细胞的丰度随着分级和基因改变（如PDGFRA扩增）而增加。

纵向分析强调了两种主要的恶性细胞状态转变模式。首先，在获得复发相关遗传事件的胶质瘤中，谱系分化减少和复发时增殖性恶性细胞增加。这些包括治疗相关的超突变，增加的拷贝数变化和细胞周期改变。其次，间充质样状态丰度的增加与获得性遗传改变无关，而是与巨噬细胞表达的升高相吻合。总的来说，他们的发现提供了一个综合模型，追踪在IDH突变型胶质瘤疾病进展过程中形成细胞状态的细胞内在和外在因素。

研究人员表示，异柠檬酸脱氢酶（IDH）突变的胶质瘤是恶性脑肿瘤，通常发生在成年早期到中期，并且几乎总是在治疗后复发。然而，在治疗过程中驱动IDH突变型胶质瘤进展的遗传和细胞状态变化仍不完全清楚。

附：英文原文

Title: Acquired genetic and cell-state changes in IDH-mutant glioma progression

Author: Johnson, Kevin C., Spitzer, Avishay, Varn, Frederick S., Nomura, Masashi, Garofano, Luciano, Chowdhury, Tamrin, Lipsa, Anuja, Zhang, Linbin, Fernndez, Ester Calvo, Barak, Tanyeri, Gulhan Ercan-Sencicek, A., Peksen, Ayse Buket, Anderson, Kevin J., Tesileanu, C. Mircea S., Amin, Samirkumar B., Kocakavuk, Emre, Zhao, Dacheng, DAngelo, Fulvio, Migliozzi, Simona, Bussema, Lillian, Gritsch, Simon, Moon, Hyo-Eun, Paek, Sun Ha, Bielle, Franck, Laurenge, Alice, Di Stefano, Anna Luisa, Mathon, Bertrand, Picca, Alberto, Sanson, Marc, Hau, Ann-Christin, Hertel, Frank, Grzyb, Kamil, Zhao, Zheng, Wang, Qianghu, Jiang, Tao, Miller, Julie J., Wakimoto, Hiroaki, Cahill, Daniel P., Moliterno, Jennifer, Gnel, Murat, Hermes, Beth, Sanai, Nader, Golebiewska, Anna, Niclou, Simone P., Huse, Jason, Alfred Yung, W. K., Lasorella, Anna, Suv, Mario L., Iavarone, Antonio, Tirosh, Itay, Verhaak, Roel G. W.

Issue&Volume: 2026-06-03

Abstract: Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment1,2. However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial–neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma3,4. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.

DOI: 10.1038/s41586-026-10612-6

Source: https://www.nature.com/articles/s41586-026-10612-6