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恶性A-to-IRNA编辑由ADAR1驱动T细胞急性淋巴细胞白血病复发通过减弱dSRNA传感

Maria Rivera^1,2, Haoran Zhang^1,2, Jessica Pham¹

¹Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Research square

|July 3, 2023

概括

RNA编辑酶ADAR1对于白血病发起细胞 (LICs) 的自我更新至关重要,它通过阻止双链RNA (dsRNA) 的感知. 向ADAR1提供了一种有希望的策略,以消除LIC并预防T细胞急性淋巴细胞白血病 (T-ALL) 复发.

科学领域:

分子生物学分子生物学
免疫学免疫学免疫学
在瘤学瘤学.

背景情况:

白血病发起细胞 (LICs) 驱动白血病的复发和治疗抵抗.
识别控制LIC自我更新的因素对于有效的治疗策略至关重要.
异常RNA修饰与各种癌症有关,包括T细胞急性淋巴细胞白血病 (T-ALL).

研究的目的:

研究RNA编辑酶ADAR1在LIC自我更新中的作用.
阐明ADAR1影响LIC干性的机制.
评估ADAR1作为T-ALL的治疗点.

主要方法:

在T-ALL患者样本中分析ADAR1表达和RNA编辑.
在T-ALL细胞系和患者衍生异种移植 (PDX) 模型中对ADAR1的抑制.
评估LIC的自我更新能力和瘤生长.
研究ADAR1,dsRNA和天生的免疫传感器MDA5.5之间的相互作用.

主要成果:

ADAR1是一种关键的干性因子,通过抑制dSRNA传感来促进LIC自我更新.
由ADAR1编辑的提升的腺至氨酸 (A-to-I) 在复发的T-ALL中很常见.
在T-ALL PDX模型中,ADAR1倒置抑制LIC自我更新,并延长存活时间.
ADAR1编辑免疫性dsRNA并将核中的未编辑的dsRNA隔离起来,以逃避MDA5的检测.
在T-ALL中,MDA5水平决定了对ADAR1-MDA5轴的依赖.

结论:

ADAR1通过限制内源性dSRNA的感知功能作为自我更新因子.
向ADAR1是一种潜在的治疗策略,可以消除T-ALL LIC并预防复发.

关键词:

在 ADAR1 中,ADAR1 是编辑RNA的RNA编辑所有的T-ALL.

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