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. Overall design: Ba/F3 cells infected with corresponding lentivirus

急性淋巴细胞白血病（Acute lymphoblastic leukemia, ALL）是儿童白血病中最为常见的类型，其发生直接由染色体重排诱导的融合基因驱动。与野生型基因相比，各类致癌融合基因（oncofusions）呈现出更高的表达水平与持续增强的致癌功能，进而推动肿瘤发生进程。然而，染色体重排如何导致融合基因功能增强的潜在机制，在很大程度上仍不甚明晰。与此同时，尽管大规模测序技术已揭示了大量融合事件，但绝大多数融合事件的功能内涵仍未明确。本研究首次揭示，mRNA稳定性增强是致癌融合基因（oncofusions）驱动肿瘤发生的一种常见且关键的机制，经典PAX5融合基因便是此类代表。基于这一普适性机制，我们鉴定出一种新型致癌融合基因STK38-PXT1，该融合基因可上调STK38的mRNA水平，并直接推动急性淋巴细胞白血病的发生发展。从机制上看，致癌融合基因的mRNA稳定性提升源于其N6-甲基腺嘌呤（m6A）修饰增强，这一现象主要归因于两种模式：一是“基因截短”（如PAX5融合），二是“伙伴基因协同”（如STK38-PXT1）。此外，IGF2BP3作为在这类融合基因驱动的白血病中特异性上调的m6A阅读蛋白，对于维持致癌融合基因的高mRNA稳定性至关重要。我们进一步提出，维奈克拉（venetoclax）可作为一款创新且已实现临床可用的药物，用于治疗携带这些高稳定性致癌融合基因的急性淋巴细胞白血病患者。本研究不仅阐明了mRNA稳定化是融合基因驱动肿瘤发生的通用机制，还为急性淋巴细胞白血病患者提供了极具前景的治疗靶点与干预策略。总体实验设计：将对应慢病毒（lentivirus）感染Ba/F3细胞。