一种可用药物的瘤抑制剂和白血病干细胞标记物
Yi Pan1,2, Xiaduo Meng1,2, Chen Wang1,2
1Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
bioRxiv : the preprint server for biology
|January 7, 2026
概括
耐化疗急性髓性白血病 (AML) 复发是由于缺乏AT2R的白血病干细胞 (LSCs) 导致的. 用布洛克西布提德 (C21) 向AT2R抑制AML的进展,并增强化疗,为AML复发患者提供希望.
科学领域:
- 血液学 血液学 血液学
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 急性髓性白血病 (AML) 由于耐化疗白血病干细胞 (LSCs) 经常复发.
- 复发性AML的预后不好,对当前的疗法没有反应.
- 确定AML的新疗法目标至关重要.
研究的目的:
- 通过使用大语言模型 (LLM) 代理来提名AML的可用药物治疗点.
- 调查 ангиотензинII受体2型 (AGTR2/AT2R) 在AML病变和LSC功能中的作用.
- 评估AT2R激动剂在AML模型中的治疗潜力.
主要方法:
- 开发了一种LLM代理,集成多模式数据以识别治疗点.
- 在68个初级人类AML样本和21个患者衍生异种移植 (PDX) 模型上进行功能性研究.
- 分析AT2R表达,染色质重组和AGTR2.2的表观遗传沉默.
- 用Agtr2敲击或强制表达的小鼠AML模型.
- 用Buloxibutid (C21) 治疗AML PDX模型,这是一个AT2R激动剂.
主要成果:
- 更高的AGTR2 (AT2R) 表达与更好的化疗反应和AML的生存相关.
- 白血病干细胞 (LSCs) 始终缺乏AT2R表达,并在化疗后得到丰富.
- 表观遗传沉默,而不是突变,被确定为AMLAT2R下调的机制.
- 在小鼠模型中强制AT2R表达延迟了AML的进展,降低了LSC的频率,并抑制了干部.
- 布洛西布提德 (C21) 显著抑制了AML的进展,并提高了化疗的疗效,特别是在复发的AML中.
结论:
- 缺少AT2R是LSC的标志物,AT2R在AML中起着瘤抑制作用.
- 对AGTR2的表观遗传沉默有助于AT2R下调和AML复发.
- 用布洛克西布提德 (C21) 等激动剂向AT2R是一种有前途的AML治疗策略,特别是复发病例.
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