Identification of GSE1 as a PAX5 fusion partner and characterization of PAX5 fusion signature in B-cell acute lymphoblastic leukaemia.

In B-cell acute lymphoblastic leukaemia (B-ALL), paired box 5 (PAX5) rearrangement (PAX5-r) represents a critical genetic driver. Here, we report the identification of an in-frame PAX5::GSE1 fusion gene in a patient with B-ALL. Functional characterization revealed that the PAX5::GSE1 protein localizes to the nucleus, promotes cell proliferation and suppresses wild-type PAX5 transcriptional activity. Notably, its transcript levels correlated with treatment response, supporting its utility as a minimal residual disease biomarker. By analysing 330 patients with PAX5-r B-ALL, we identified 76 distinct in-frame partner genes and delineated their breakpoint characteristics. Integrated multi-cohort transcriptomic analysis further revealed that PAX5-r induces a convergent expression profile relative to healthy individuals, characterized by dysregulation of the retinoblastoma transcriptional corepressor 1 (RB1) and p53 pathways and overexpression of nucleophosmin 1 (NPM1). These findings help to clarify core molecular mechanisms underlying PAX5-r-driven leukaemogenesis and highlight potential therapeutic vulnerabilities.