This article investigates the molecular mechanisms driving Group 3 medulloblastoma (MB), an aggressive pediatric brain tumor. It establishes a noncanonical role for the transcription factor OTX2 in regulating alternative splicing, which is crucial for maintaining the tumor's stem cell state. Specifically, the study demonstrates that OTX2 interacts with the large assembly of splicing regulators (LASR) complex to control a pro-tumorigenic splicing program, partially independent of its DNA-binding function. Targeting one of the key OTX2-regulated differentially spliced genes, PPHLN1, through splice-blocking, effectively reduced tumor growth and enhanced survival in mouse models. This research suggests that OTX2-mediated alternative splicing represents a vital determinant of cell fate decisions in Group 3 MB progression and offers a promising new therapeutic target.
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