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BCAT1有助于TCI耐药性CML的发展

Yu Jiang¹, Difan Zhang¹, Xiaoxiao He¹

¹Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.

Cellular oncology (Dordrecht, Netherlands)

|October 16, 2024

概括

准分支链氨基酸转氨酶1 (BCAT1) 信号,有效地抑制了耐氨酸激酶抑制剂的慢性髓性白血病 (CML). 这项研究揭示了BCAT1

科学领域:

生物化学生物化学
在瘤学瘤学.
分子生物学分子生物学

背景情况:

慢性髓性白血病 (CML) 治疗用氨酸激酶抑制剂 (TKIs) 是有效的,但耐药性发生在15-17%的患者.
分支链氨基酸 (BCAA) 代谢与TKI耐药性有关,但潜在的机制尚不清楚.
在BCAA代谢中的酶BCAT1,在CML病原和TKI耐药性中起着未知的作用.

研究的目的:

调查BCAT1在白血病发生中的作用和TKI在CML中的耐药性.
阐明BCAA/BCAT1信号传递对TCI耐药性CML有所贡献的分子机制.

主要方法:

通过细胞增殖,殖民地形成和体内移植试验,评估了白血病发生中的BCAT1功能.
采用定量实时PCR,西部涂抹,RNA测序和体外BCAA刺激来分析分子机制.
研究了BCAT1敲除对TCI耐药CML细胞系和小鼠TCI耐药CML模型的影响.

主要成果:

在小鼠和人类TKI抗性CML细胞中,BCAT1的含量很高.
在BCR-ABL^T315I诱导的小鼠模型中,BCAT1敲除显著取消了白血病,并减少了人类细胞系的增殖.
BCAA/BCAT1信号传递促进了CREB酸化,这对于维持TKI耐性CML至关重要;它的阻断抑制了体外和体内白血病发生.

结论:

BCAA/BCAT1信号在TKI耐药性CML的发展中起着至关重要的作用.
向BCAA/BCAT1信号是一种有前途的治疗策略,可以克服CML中TKI耐药性.

关键词:

BCAA 的代谢 BCAA 的代谢这是一个BCAT1BCAT1BCAT1BCAT1 在CML中,CML是CML.TKI 阻力阻力的 TKI 阻力.

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