Sang Xu, Guan Yanchun, Jiang Mengying, Chen Xin, Zhang Zhen, Peng Wansheng, Wu Yumeng
Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
Department of Pediatrics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China.
J Biol Chem. 2025 May 30;301(7):110321. doi: 10.1016/j.jbc.2025.110321.
This research utilized multiomics data to elucidate the molecular mechanisms of chemotherapy resistance in pediatric B-cell acute lymphoblastic leukemia driven by the MLL-AF9 fusion gene. Transcriptome data from B-ALL patients in the Gene Expression Omnibus and Therapeutically Applicable Research to Generate Effective Treatments databases were analyzed using weighted gene coexpression network analysis, 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.
本研究利用多组学数据来阐明由MLL-AF9融合基因驱动的小儿B细胞急性淋巴细胞白血病化疗耐药的分子机制。使用加权基因共表达网络分析对基因表达综合数据库和治疗应用研究以生成有效治疗方法数据库中B-ALL患者的转录组数据进行分析，确定IGFBP7为与MLL-AF9重排相关的关键基因。MLL-AF9融合上调IGFBP7，激活ABCB1转运蛋白和DNA-PKcs介导的非同源末端连接（NHEJ）修复途径，从而促进化疗耐药。体外实验表明，过表达MLL-AF9的B-ALL细胞对阿霉素（DOX）、环磷酰胺（CTX）和顺铂（DDP）的敏感性降低。蛋白质组学和功能分析证实MLL-AF9阳性细胞中ABCB1和DNA-PKcs表达升高，增强了DNA修复并抑制了细胞凋亡。在体外和体内模型中，AB C转运蛋白抑制剂维拉帕米和NHEJ抑制剂NU7441有效逆转了化疗耐药。这些发现突出了MLL-AF9在通过ABCB1和NHEJ途径介导化疗耐药中的作用，为MLL-AF9阳性B-ALL提供了潜在的治疗靶点。
