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Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia
Cancer Cell ( IF 48.8 ) Pub Date : 2023-06-08 , DOI: 10.1016/j.ccell.2023.05.002
Vanessa M Conn 1 , Marta Gabryelska 2 , John Toubia 3 , Kirsty Kirk 2 , Laura Gantley 2 , Jason A Powell 4 , Gökhan Cildir 5 , Shashikanth Marri 2 , Ryan Liu 2 , Brett W Stringer 2 , Scott Townley 2 , Stuart T Webb 2 , He Lin 2 , Saumya E Samaraweera 5 , Sheree Bailey 6 , Andrew S Moore 7 , Mellissa Maybury 8 , Dawei Liu 5 , Alex D Colella 9 , Timothy Chataway 9 , Craig T Wallington-Gates 10 , Lucie Walters 11 , Jane Sibbons 12 , Luke A Selth 13 , Vinay Tergaonkar 14 , Richard J D'Andrea 5 , Stuart M Pitson 4 , Gregory J Goodall 4 , Simon J Conn 1
Affiliation  

The first step of oncogenesis is the acquisition of a repertoire of genetic mutations to initiate and sustain the malignancy. An important example of this initiation phase in acute leukemias is the formation of a potent oncogene by chromosomal translocations between the mixed lineage leukemia (MLL) gene and one of 100 translocation partners, known as the MLL recombinome. Here, we show that circular RNAs (circRNAs)—a family of covalently closed, alternatively spliced RNA molecules—are enriched within the MLL recombinome and can bind DNA, forming circRNA:DNA hybrids (circR loops) at their cognate loci. These circR loops promote transcriptional pausing, proteasome inhibition, chromatin re-organization, and DNA breakage. Importantly, overexpressing circRNAs in mouse leukemia xenograft models results in co-localization of genomic loci, de novo generation of clinically relevant chromosomal translocations mimicking the MLL recombinome, and hastening of disease onset. Our findings provide fundamental insight into the acquisition of chromosomal translocations by endogenous RNA carcinogens in leukemia.



中文翻译:

环状RNA驱动白血病MLL重组组内的致癌染色体易位

肿瘤发生的第一步是获得一系列基因突变来引发和维持恶性肿瘤急性白血病这一起始阶段的一个重要例子是,混合谱系白血病 ( MLL ) 基因与 100 个易位伙伴之一(称为 MLL 重组组)之间的染色体易位形成了强效癌基因。在这里,我们表明,环状 RNA (circRNA)——一类共价闭合、选择性剪接的 RNA 分子——在 MLL 重组组中富集,可以结合 DNA ,在其同源位点形成 circRNA:DNA 杂合体(circR 环)。这些 circR 环促进转录暂停、蛋白酶体抑制、染色质重组和 DNA 断裂。重要的是,在小鼠白血病异种移植模型中过度表达 circRNA会导致基因组位点的共定位、模仿MLL重组组的临床相关染色体易位的从头生成以及疾病发作的加速。我们的研究结果为白血病中内源性 RNA 致癌物引起的染色体易位提供了基础见解。

更新日期:2023-06-08
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