Chromosomal rearrangement-enhanced mRNA stability drives the carcinogenicity of oncofusion in pediatric leukemia

Acute lymphoblastic leukemia (ALL), the most common type of pediatric leukemia, is directly driven by chromosomal rearrangement-induced fusion genes. Compared to wild-type genes, various oncofusions exhibit heightened expression levels and continuous enhanced function to drive tumorigenesis. However, the underlying mechanism by which chromosomal rearrangements lead to functional enhancement remains largely elusive. Meanwhile, although large-scale sequencing has illuminated numerous fusion events, most of their functional implications is unknown. Here, we uncover for the first time that mRNA stability enhancement is a common and important tumorigenic mechanism for oncogenic fusions, such as classical PAX5 fusions. Based on this universal mechanism, we have identified a novel oncogenic fusion, STK38-PXT1, which exhibits upregulated STK38 mRNA levels and directly drives the development of ALL. Mechanically, the increased mRNA stability arises from enhanced m6A modification of oncofusions, which is primarily due to “gene truncation”, such as PAX5 fusion, and “partner collaboration”, such as STK38-PXT1. Furthermore, IGF2BP3, an m6A reader specifically up-regulated in these fusions-driven leukemia, is crucial for maintaining the high mRNA stability of oncofusions. We further propose venetoclax as an innovative and clinically available drug for ALL driven by these high-stability oncofusions. Our study not only sheds light on mRNA stabilization as a general mechanism for fusions to drive tumorigenesis, but also presents a promising therapeutic drug target and strategy for ALL patients.