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尿液代谢作为一种可向的代谢阿基里斯脚跟,用于抗化疗的B-ALL

Yuxuan Liu¹, Haowen Jiang², Jingjing Liu³

¹Division of Hematology, Oncology, and Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, CA.

bioRxiv : the preprint server for biology

|February 20, 2025

概括

在B细胞急性淋巴细胞白血病 (B-ALL) 细胞中的活性信号增加了葡萄糖的使用和尿液依赖. 向二基酸脱酶 (DHODH) 显示出治疗化疗耐药B-ALL的前景.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
在瘤学瘤学.

背景情况:

B细胞急性淋巴细胞白血病 (B-ALL) 的复发是一个重大挑战,与化疗耐药性有关.
之前的研究独立地确定了激活的B细胞信号传递和增加的葡萄糖代谢作为B-ALL复发风险的因素.

研究的目的:

研究具有活性信号的B-ALL细胞的代谢依赖性.
探索尿素合成在B-ALL生存和复发中的作用.
为了评估二酸酸脱酶 (DHODH) 作为B-ALL中的治疗点.

主要方法:

利用同位素追踪和代谢流量分析来研究B-ALL细胞代谢.
评估了缺乏葡萄糖和尿素补充对B-ALL细胞的影响.
研究了碳酸合成酶 (CAD) 和二酸脱酶 (DHODH) 在尿素合成中的作用.
在体外和体外模型中使用了DHODH抑制剂BAY2402232.

主要成果:

具有高酸化核糖体蛋白S6 (pS6+) 的B-ALL细胞表现出高的糖解和对核酸合成的葡萄糖的依赖.
尿素,而不是 purin 或 pyrimidine,拯救 pS6+ 细胞免受葡萄糖剥夺,表明基本性.
在pS6+细胞中的活性信号通过CAD酸化调节尿素合成.
增加的DHODH表达与B-ALL复发和较低的存活率相关.
通过BAY2402232抑制DHODH在体外和体内有效地杀死pS6+ B-ALL细胞,延长存活时间.

结论:

在B-ALL细胞中,活性信号产生了对尿素合成的依赖,与复发风险有关.
向DHODH为抗化疗性B-ALL提供了一种新的治疗策略.

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