2. Academic Validation
  3. Oncogenic fusions converge on shared mechanisms in initiating astroblastoma

Oncogenic fusions converge on shared mechanisms in initiating astroblastoma

  • Nature. 2025 Jul;643(8071):551-561. doi: 10.1038/s41586-025-08981-5.
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
Affiliations

Affiliations

  • 1 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 2 Chinese Institute for Brain Research, Beijing, China.
  • 3 Department of Molecular Biology and Biochemistry, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
  • 4 Eight-year Medical Doctor Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 Beijing Institute for Brain Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. shiwei@cibr.ac.cn.
  • 6 Chinese Institute for Brain Research, Beijing, China. shiwei@cibr.ac.cn.
  • 7 Department of Molecular Biology and Biochemistry, State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China. yuy@ibms.pumc.edu.cn.
  • # Contributed equally.
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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