Oncogenic fusions converge on shared mechanisms in initiating astroblastoma

Yixing Shi, Qianqian Sun, Fuchuan Jia, Xiangyu Xie, Xiangyu Zhou, Rong Guo, Yangfan Zeng, Shanshan Chen, Zhenzhen Guo, Wenli Sun, Tong Guo, Yu Xia, Wenlong Li, Li Zhang, Wei Shi () and Yang Yu ()
Additional contact information
Yixing Shi: Chinese Academy of Medical Sciences and Peking Union Medical College
Qianqian Sun: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
Fuchuan Jia: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
Xiangyu Xie: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiangyu Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College
Rong Guo: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
Yangfan Zeng: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College
Shanshan Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhenzhen Guo: Chinese Academy of Medical Sciences and Peking Union Medical College
Wenli Sun: Chinese Academy of Medical Sciences and Peking Union Medical College
Tong Guo: Chinese Academy of Medical Sciences and Peking Union Medical College
Yu Xia: Chinese Academy of Medical Sciences and Peking Union Medical College
Wenlong Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Li Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Wei Shi: Chinese Academy of Medical Sciences and Peking Union Medical College
Yang Yu: Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College

Nature, 2025, vol. 643, issue 8071, 551-561

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08981-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:643:y:2025:i:8071:d:10.1038_s41586-025-08981-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08981-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().