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.
ZFTA-RELA是儿童幕上室管膜瘤中最常见的复发性遗传改变，且足以在小鼠中启动肿瘤形成。尽管具有致癌潜力，ZFTA-RELA几乎仅见于儿童室管膜瘤，肿瘤明确位于中枢神经系统的幕上脑区。我们提出，大脑发育过程中特定的染色质模块可被开放，从而使不同的细胞谱系程序直接面临由ZFTA-RELA诱导转化的风险。为验证这一假设，我们对发育中的小鼠前脑进行了转座酶可及染色质与RNA的单核联合测序，并与ZFTA-RELA驱动的小鼠及人类室管膜瘤进行比较。结果表明，存在于瞬时祖细胞中、受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。ZFTA-RELA或其他靶向融合癌蛋白的PLAG/L家族基序结合这一染色质网络后，可导致致癌位点的染色质持续开放及癌基因表达。小鼠和人类ZFTA-RELA室管膜瘤的跨物种分析揭示了显著的细胞类型异质性，提示不完全的神经发生和胶质发生分化，其中一小部分循环祖细胞样或放射状胶质细胞样细胞建立了假定的肿瘤细胞层级。体内谱系示踪研究发现，肿瘤克隆可主导性驱动肿瘤生长并建立整个室管膜瘤的细胞层级。这些发现揭示了对于融合癌蛋白驱动的转化至关重要的发育表观基因组状态，并阐明了这些状态如何持续塑造肿瘤的进展。
Dominant clones leverage developmental epigenomic states to drive ependymoma
肿瘤(癌症)患者之家