Yixing Shi # 1 2, Qianqian Sun # 3, Fuchuan Jia 3, Xiangyu Xie 1 2, Xiangyu Zhou 1 2, Rong Guo 3, Yangfan Zeng 3, Shanshan Chen 1 2, Zhenzhen Guo 1 2, Wenli Sun 1 2, Tong Guo 1 2, Yu Xia 4, Wenlong Li 1 2, Li Zhang 1 2, Wei Shi 5 6, Yang Yu 7

Nature. 2025 Jul;643(8071):551-561.

PMID: 40369078 DOI: 10.1038/s41586-025-08981-5

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.

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