Chromosomal rearrangement-enhanced mRNA stability drives the oncogenic potential of fusion genes in pediatric leukemia.

Acute lymphoblastic leukemia (ALL), the most common type of pediatric leukemia, is frequently driven by fusion genes generated by chromosomal rearrangements. Compared with wild-type genes, many oncogenic fusions show increased expression and sustained functional activity that drives tumorigenesis. However, the mechanisms by which chromosomal rearrangements lead to functional enhancement remain largely elusive. In addition, although large-scale sequencing has identified numerous fusion events, the functional significance of most remains unclear. Here, we demonstrate that enhanced mRNA stability represents an important tumorigenic mechanism for oncogenic fusions, including classical PAX5 fusions. Based on this mechanism, we characterize a novel oncogenic fusion, STK38-PXT1, which exhibits upregulated STK38 mRNA levels and drives the development of ALL. Mechanistically, the increased mRNA stability results primarily from enhanced m6A modification of oncogenic fusions, which is attributable to "gene truncation" (as in PAX5 fusions) and "partner collaboration" (as in STK38-PXT1). Furthermore, the m6A reader IGF2BP3 is crucial for maintaining the high mRNA stability of oncogenic fusions. We further propose venetoclax as an innovative and clinically available therapy for ALL driven by these oncogenic fusions characterized by high mRNA stability. Our study not only highlights mRNA stabilization as a crucial mechanism by which oncogenic fusions to drive tumorigenesis, but also presents a promising therapeutic strategy for patients with ALL.