SON is a key splicing factor regulating B-ALL leukemogenesis through SREBP1-mediated fatty acid synthesis

Introduction Relapse of B-cell acute lymphoblastic leukemia (B-ALL) remains a major challenge, emphasizing the urgent need for effective treatment strategies. SON, a DNA/RNA-binding protein, is implicated in various malignancies; however, its role and therapeutic potential in relapsed B-ALL remain unexplored. Objectives This study aimed to elucidate the functional role of SON in relapsed pediatric B-ALL to provide valuable insights for the development of therapeutic strategies for treating the disease. Methods Multiple transcriptomic analyses were conducted using publicly available datasets to assess SON and SREBF1 expression in pediatric B-ALL. To investigate the effect of SON inhibition, we measured cell proliferation, mRNA expression, apoptosis, colony formation, fatty acid levels, RNA splicing, and leukemia engraftment in vivo . Results SON was significantly upregulated in pediatric B-ALL, particularly in relapsed cases. In vitro studies with SON shRNAs demonstrated that SON depletion reduced pediatric B-ALL cell proliferation and clonogenicity and induced apoptosis, while also impairing leukemic engraftment in vivo . Transcriptomic and splicing analyses revealed that SON knockdown induced intron retention in fatty acid metabolism-related genes, including SREBF1 (encoding SREBP1). Mechanistically, SON directly bound to multiple exon–intron junctions of SREBF1 pre-mRNA, ensuring proper RNA splicing and stability. Moreover, SON and SREBF1 were co-expressed and upregulated in pediatric B-ALL samples at relapse. Pharmacological inhibition of SREBPs with fatostatin and genetic inhibition of SREBF1 recapitulated the effects of SON depletion, indicating the critical roles of the SON-SREBP1 axis in leukemogenesis. In vivo studies demonstrated that fatostatin treatment significantly impaired pediatric B-ALL engraftment and prolonged mouse survival, with maximal therapeutic benefits observed upon combined SON depletion and fatostatin treatment. Conclusion These findings identified SON as a key regulator of B-ALL leukemogenesis through SREBP1-mediated fatty acid metabolism, suggesting that targeting SON or its downstream pathways may constitute a promising therapeutic strategy for relapsed B-ALL.