中国医学科学院于洋团队的一项最新研究探明了致瘤融合在星形母细胞瘤的启动机制上趋于一致。2025年5月14日出版的《自然》杂志发表了这项成果。

在小鼠实验中，研究组发现这两种与ABM相关的离子聚集在相似的分子活动上，并特异性地在腹侧端脑神经祖细胞中引发恶性肿瘤。BEND2和CXXC5识别相似的DNA基序，这表明它们在下游基因调控上趋同。MN1-BEND2在腹端脑神经祖细胞中的表达导致细胞增殖异常，分化受损，细胞在血管周围占据模式，使人联想到ABM，并获得ABM相关的转录特征。相反，MN1-BEND2在背端脑神经祖细胞中的表达会导致广泛的细胞死亡。这种细胞类型特异性恶性肿瘤依赖于OLIG2的表达。

在机制上，两种与ABM相关的融合蛋白（MN1-BEND2和MN1-CXXC5）诱导重叠的转录反应，包括可用于治疗的PDGFRα途径的激活。总的来说，他们的数据表明，不同的与ABM相关的基因上调共享的转录网络，破坏腹端脑神经祖细胞的正常发育，从而导致致癌转化。这些发现揭示了靶向ABM治疗的新途径。

据介绍，染色体重排和基因突变是许多癌症发展的初始事件。星形母细胞瘤（Astroblastoma， ABM）是一种细胞起源未知且具有治疗挑战性的脑癌，与多种框架内基因相关，包括MN1-BEND2和MN1-CXXC5。然而，目前尚不清楚这些基因是否与肿瘤发生有关。

附：英文原文

Title: Oncogenic fusions converge on shared mechanisms in initiating astroblastoma

Author: Shi, Yixing, Sun, Qianqian, Jia, Fuchuan, Xie, Xiangyu, Zhou, Xiangyu, Guo, Rong, Zeng, Yangfan, Chen, Shanshan, Guo, Zhenzhen, Sun, Wenli, Guo, Tong, Xia, Yu, Li, Wenlong, Zhang, Li, Shi, Wei, Yu, Yang

Issue&Volume: 2025-05-14

Abstract: Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a brain cancer of unknown cellular origin and challenging to treat, is associated with diverse in-frame gene fusions, including MN1-BEND2 and MN1-CXXC5 (refs. 1,2). However, it remains unclear whether these gene fusions contribute to tumorigenesis. Here we show in mice that these two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognize similar DNA motifs, which indicates a convergence on downstream gene regulation. Expression of MN1-BEND2 in ventral telencephalon neural progenitors results in aberrant cell proliferation, impaired differentiation, a perivascular occupancy pattern of cells reminiscent of ABM and acquisition of an ABM-associated transcriptional signature. By contrast, MN1-BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type-specific malignancy depends on OLIG2 expression. Mechanistically, both ABM-associated fusion proteins (MN1–BEND2 and MN1–CXXC5) induce overlapping transcriptional responses, including the activation of a therapeutically targetable PDGFRα pathway. Collectively, our data suggest that distinct ABM-associated fusions upregulate shared transcriptional networks to disrupt the normal development of ventral telencephalon neural progenitors, which leads to oncogenic transformation. These findings uncover new avenues for targeted ABM treatment.

DOI: 10.1038/s41586-025-08981-5

Source: https://www.nature.com/articles/s41586-025-08981-5