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.
