Molecular Insights into Chemotherapy Resistance Mediated by MLL-AF9 Fusion Gene in Pediatric B-Cell Acute Lymphoblastic Leukemia.

This research utilized multi-omics data to elucidate the molecular mechanisms of chemotherapy resistance in pediatric B-cell acute lymphoblastic leukemia (B-ALL) driven by the MLL-AF9 fusion gene. Transcriptome data from B-ALL patients in the Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases were analyzed using weighted gene co-expression network analysis (WGCNA), identifying IGFBP7 as a critical gene associated with MLL-AF9 rearrangement. The MLL-AF9 fusion upregulated IGFBP7, activating ABCB1 transporters and the DNA-PKcs-mediated non-homologous end-joining (NHEJ) repair pathway, thereby promoting chemoresistance. In vitro experiments demonstrated that MLL-AF9-overexpressing B-ALL cells exhibited reduced sensitivity to doxorubicin (DOX), cyclophosphamide (CTX), and cisplatin (DDP). Proteomic and functional assays confirmed elevated ABCB1 and DNA-PKcs expression in MLL-AF9 positive cells, enhancing DNA repair and suppressing apoptosis. Chemoresistance was effectively reversed by the ABC transporter inhibitor Verapamil and the NHEJ inhibitor NU7441 in in vitro and in vivo models. These findings highlight MLL-AF9's role in mediating chemoresistance via ABCB1 and the NHEJ pathways, offering potential therapeutic targets for MLL-AF9-positive B-ALL.