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U2af1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2021 , DOI: 10.1172/jci141401
Brian A Wadugu 1 , Sridhar Nonavinkere Srivatsan 1 , Amanda Heard 1 , Michael O Alberti 2 , Matthew Ndonwi 1 , Jie Liu 1 , Sarah Grieb 1 , Joseph Bradley 1 , Jin Shao 1 , Tanzir Ahmed 1 , Cara L Shirai 1 , Ajay Khanna 1 , Dennis L Fei 3, 4 , Christopher A Miller 1 , Timothy A Graubert 5 , Matthew J Walter 1
Affiliation  

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant–expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of WT U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1(S34F)-expressing cells were also more sensitive to reduced expression of WT U2AF1 than nonmutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the WT U2af1 allele was deleted compared with when it was not deleted. These results suggest that selectively targeting the WT U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

中文翻译:

U2af1 是小鼠造血癌细胞存活所需的单倍体必需基因

剪接体基因U2AF1的体细胞突变在骨髓增生异常综合征患者中很常见。编码最常见氨基酸取代的U2AF1突变总是杂合的,并且保留的 WT 等位基因被表达,这表明突变的造血细胞可能需要残留的 WT 等位基因才能存活。我们显示U2af1杂合基因敲除小鼠的造血和 RNA 剪接与对照小鼠相似,但在表达 U2AF1(S34F) 杂合突变体的造血细胞(即半合突变体)中 WT 等位基因的缺失是致命的。这些结果证实了 U2AF1 突变造血细胞依赖于 WT U2AF1 的表达在体内存活,并且U2AF1是一个单倍体必需的癌症基因。与非突变细胞相比,表达突变 U2AF1(S34F) 的细胞对 WT U2AF1 表达降低也更敏感。此外,与未删除 WT U2af1 等位基因相比,移植了表达突变 U2AF1 的白血病细胞的小鼠在删除 WT U2af1等位基因后显着降低了肿瘤负荷并提高了存活率。这些结果表明,选择性靶向杂合突变细胞中的 WT U2AF1等位基因可以诱导癌细胞死亡,并成为携带U2AF1突变患者的治疗策略。
更新日期:2021-11-02
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