B-淋巴细胞转录因子的代谢守门员功能
Lai N Chan1,2, Zhengshan Chen1,2, Daniel Braas3
1Department of Systems Biology, Beckman Research Institute and City of Hope National Medical Center, Pasadena, California 91016, USA.
Nature
|February 14, 2017
概括
B淋巴细胞转录因子PAX5和IKZF1作为代谢门卫,限制B细胞发育中的能量供应. 在B型前急性淋巴细胞白血病 (ALL) 中,它们的丧失导致能量危机,突出了治疗目标.
科学领域:
- 分子生物学
- 细胞代谢
- 癌症生物学
背景情况:
- B淋巴细胞转录因子PAX5和IKZF1对于B细胞发育至关重要.
- 在B细胞前急性淋巴细胞白血病 (ALL) 中,PAX5和IKZF1的突变很常见,但它们的作用尚不清楚.
- 了解这些因素在ALL中的作用对于向治疗至关重要.
研究的目的:
- 阐明PAX5和IKZF1在B淋巴细胞中调节细胞代谢中的作用.
- 确定这些转录因子影响ALL的能量供应和细胞命运的机制.
- 探索潜在的针对B ALL前代谢途径的治疗策略.
主要方法:
- 用测序 (ChIP-seq) 和RNA测序进行染色体免疫沉.
- 代谢分析,包括葡萄糖摄取和ATP水平测量.
- 使用转基因前BALL小鼠模型进行CRISPR/Cas9查和体内研究.
主要成果:
- PAX5和IKZF1强制执行一种代谢程序,限制葡萄糖和能量供应,导致能量剥夺和AMPK激活.
- 在B ALL前,PAX5/ IKZF1功能的丧失导致葡萄糖吸收和ATP水平的增加.
- 确定NR3C1,TXNIP和CNR2是这种代谢限制的关键媒介.
- 向TXNIP,CNR2和AMPK与葡萄皮质类药物协同作用,具有治疗潜力.
结论:
- 乙淋巴细胞转录因子作为代谢守门人,控制细胞ATP水平以防止恶性转变.
- 这些代谢守门者的失调是B ALL前病变的一个关键事件.
- 针对代谢途径,特别是TXNIP,CNR2和AMPK,为ALL提供了一个有前途的治疗途径.
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