圣犹达儿童研究医院Stephen C. Mack小组的研究显示，显性克隆利用发育表观基因组状态来驱动室管膜瘤。2026年3月25日，国际知名学术期刊《自然》发表了这一成果。

研究小组提出，在大脑发育过程中可获得的特定染色质模块将使不同的细胞谱系程序面临ZR转化的直接风险。为了验证这一假设，课题组对发育中的小鼠前脑与ZR驱动的小鼠和人类EPN进行了转座酶可及的染色质和RNA （snMultiome）测序的单核试验。研究人员证明了瞬时祖细胞中存在的由PLAG/L家族转录因子调控的特定发育谱系程序具有肿瘤转化的风险。该染色质网络被ZR或其他PLAG/L家族基元结合以靶定离子癌蛋白，导致染色质在致癌位点和癌基因表达上的持续可及性。

小鼠和人类ZR EPN的跨物种分析显示了显著的细胞类型异质性，表明神经源性和胶质源性分化不完全，一小部分循环祖细胞样细胞或放射状胶质样细胞建立了假定的肿瘤细胞等级。体内谱系追踪研究发现，肿瘤克隆积极主导肿瘤生长，并建立了整个EPN细胞层次结构。这些发现确定了对肿瘤蛋白驱动转化至关重要的发育表观基因组状态，并显示了这些状态如何继续影响肿瘤的进展。

据介绍，ZFTA–RELA是儿科幕上室管膜瘤（EPN）中最常见的基因改变，足以在小鼠中引发肿瘤。尽管具有致癌潜力，ZFTA-RELA（ZR）几乎只在儿童EPN中被观察到，肿瘤明显位于中枢神经系统的幕上脑。

附：英文原文

Title: Dominant clones leverage developmental epigenomic states to drive ependymoma

Author: Kardian, Alisha S., Sun, Hua, Ippagunta, Siri, Laboe, Nicholas, Varadharajan, Srinidhi, Yu, Kwanha, Chen, Hsiao-Chi, Emanus, Erik, Zheng, Tuyu, Deneen, Riley M., Connelly, Jon P., Wang, Yong-Dong, Zhan, Jiangshan, Liu, Hengxi, Lowe, Kimberley, Bugbee, Taylor, Pathak, Rakesh, Bland, Amanda, Mehta, Sanya, Cochiolo, Sophie, Arabzade, Amir, Holcomb, Blake, Budd, Kaitlin M., Kembuan, Gabriele, Wright, Tristen, Caesar, Emma, Park, Maxwell, Hancock, Amelia, Gee, David, Murdoch, Joel, Xiao, Yi, McBrayer, Samuel K., Merchant, Thomas E., Qi, Jun, Durbin, Adam D., Schwarz, Lindsay A., Wang, Li, Donson, Andrew M., Foreman, Nicholas K., Agnihotri, Sameer, Lavado, Alfonso, Baker, Suzanne J., Ellison, David W., Lee, Hyun Kyoung, Pruett-Miller, Shondra M., Bertrand, Kelsey C., Deneen, Benjamin, Mack, Stephen C.

Issue&Volume: 2026-03-25

Abstract: ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse and human EPN. We demonstrated that specific developmental lineage programs present in transient progenitor cells and regulated by PLAG/L family transcription factors were at risk of neoplastic transformation. Binding of this chromatin network by ZR or other PLAG/L family motifs targeting fusion oncoproteins led to persistent chromatin accessibility at oncogenic loci and oncogene expression. Cross-species analysis of mouse and human ZR EPN revealed significant cell type heterogeneity indicating incomplete neurogenic and gliogenic differentiation, with a small percentage of cycling progenitor-like or radial glial-like cells that established a putative tumour cell hierarchy. In vivo lineage tracing studies identified neoplastic clones that aggressively dominated tumour growth and established the entire EPN cellular hierarchy. These findings identify developmental epigenomic states that are critical for fusion-oncoprotein-driven transformation and show how these states continue to shape tumour progression.

DOI: 10.1038/s41586-026-10270-8

Source: https://www.nature.com/articles/s41586-026-10270-8