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在人类急性髓性白血病中识别非功能性的SING替代拼接异型

Akash R Boda^1,2, Arthur J Liu^1,2, Susana Castro-Pando^1,3

¹Immunology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, Texas.

Cancer research communications

|March 13, 2024

概括

急性髓性白血病 (AML) 通过STING转录的新替代拼接,使干扰素基因刺激器 (STING) 途径沉默. 这种机制赋予了对先天免疫激活的抵抗力,阻碍了AML患者的抗瘤免疫力.

科学领域:

免疫学免疫学免疫学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

干扰素基因刺激 (STING) 途径对于先天性免疫反应和抗瘤免疫是至关重要的.
急性髓性白血病 (AML) 通常表现为受损的STING通路激活,代表有效癌症免疫力的障碍.
了解耐药机制对于开发新型AML疗法至关重要.

研究的目的:

调查 AML 缺乏 STING 通路激活背后的机制.
为了确定对AML中STING路径抑制负责的遗传变化或调节事件.
探索针对AML治疗的STING途径的潜力.

主要方法:

利用人类AML细胞系进行STING激动剂的体外评估.
从AML细胞系cDNA中测序STING,以识别突变和拼接变异.
在初级AML样本中识别和验证了新的STING拼接异型.
将新型STING异型转化为记者细胞,以评估功能后果.

主要成果:

大多数AML细胞系对强大的STING激动剂表现出不良的I型IFN反应,表明细胞内在抑制.
在AML细胞系中确定了STING的频繁突变和异常RNA拼接.
发现了两种新的STING拼接异型,使其对激动剂刺激完全不敏感.
在初级人类AML样本中验证了这些新型异构体的表达.

结论:

对STING转录的异常替代拼接是AML中STING通路抑制的关键机制.
发现的新型STING单体表现为主导阴性,使该通路抵抗激活.
这些发现表明,AML细胞通过直接修饰来积极沉默STING通路,而不是外部因素.
治疗策略可能需要专注于克服AML中的STING耐药性,可能通过向瘤微环境.

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相关概念视频

RNA Splicing

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...

Alternative RNA Splicing

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...