Oncogenic fusions converge on shared mechanisms in initiating astroblastoma [RNA-seq of Pdgfra lineage cells]
Chromosomal rearrangements and gene fusions are the initial events in the development of many cancers. Astroblastoma (ABM), a challenging brain cancer of unknown cellular origin, is associated with diverse in-frame gene fusions, including MN1:BEND2 and MN1:CXXC5. However, it remains unclear if these gene fusions contribute to tumorigenesis. Here, we show that the two ABM-associated fusions converge on similar molecular activities and initiate malignancy specifically in ventral telencephalon neural progenitors. BEND2 and CXXC5 recognized similar DNA motifs, suggesting a convergence on downstream gene regulation. Expressing 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. In stark contrast, MN1:BEND2 expression in dorsal telencephalon neural progenitors leads to extensive cell death. This cell-type specific malignancy is dependent 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 PDGFRa pathway. Collectively, our data suggests that distinct ABM-associated fusions upregulate shared transcriptional networks, thereby disrupting the normal development of ventral telencephalon neural progenitors and culminating in oncogenic transformation. These findings uncover new avenues for targeted ABM treatment. Overall design: Analysis of Bulk RNA-seq from P4 PdgfraCreER;MB;AI14 mice and PdgfraCreER;AI14 mice.