在白血病发生过程中,GPRC5C驱动了分支链氨基酸代谢
Yu Wei Zhang1, Talia Velasco-Hernandez2, Julian Mess1,3,4,5
1Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Blood advances
|August 28, 2023
概括
白血病干细胞 (LSC) 依赖G蛋白结合受体家族C组5成员C (GPRC5C) 进行生长. 准GPRC5C-NF-κB-SLC7A5分支链氨基酸轴为急性髓性白血病 (AML) 提供了一个新的治疗策略.
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
- 代谢研究研究 代谢研究
背景情况:
- 白血病干细胞 (LSCs) 与健康的造血干细胞 (HSCs) 有共同的特征.
- G蛋白结合受体家族C组5成员C (GPRC5C) 调节HSC休眠,但其在急性髓性白血病 (AML) 中的作用尚不清楚.
- 在AML患者中高GPRC5C表达与生存率差相关.
研究的目的:
- 确定GPRC5C在AML病变发生中的作用.
- 研究GPRC5C影响AML进展的分子机制.
- 在GPRC5C信号通路中识别潜在的治疗点.
主要方法:
- 在患者AML队列中分析GPRC5C表达.
- 在体外和体内研究异位Gprc5c表达对AML侵袭的作用.
- 评估针对BCAA载体SLC7A5与JPH203对AML细胞的影响.
- 评估使用venetoclax和azacitidine的组合疗法.
主要成果:
- 宫外Gprc5c表达通过NF-κB激活促进AML的攻击性,导致细胞内分支链氨基酸 (BCAA) 的增加.
- 失去Gprc5c会逆转这种瘤代谢特征,并降低白血病发病潜力.
- 用JPH203抑制SLC7A5通过破坏氧化酸化来选择性向AML细胞,与venetoclax和azacitidine结合时有效性提高.
结论:
- 在AML中,GPRC5C-NF-κB-SLC7A5-BCAAs轴对LSC功能至关重要.
- 针对这一轴代表了AML有前途的治疗策略.
- 涉及SLC7A5抑制剂的组合疗法显示出显著的抗白血病效应.
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