小柯机器人

澳大利亚弗林德斯大学Simon J. Conn研究团队揭示，环状RNA (s)驱动白血病中的混合谱系白血病(MLL)重组组内的致癌染色体易位。相关论文发表在2023年6月8日出版的《癌细胞》杂志上。

他们发现circRNA——一个共价封闭的、可选择性剪接的RNA分子家族——在MLL重组组中富集，可以结合DNA，在其同源位点形成环状RNA:DNA杂交体(circR环)。这些环状环促进转录暂停、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表达环状RNA会导致基因组位点的共定位，模拟MLL重组组的临床相关染色体易位的重新产生，并加速疾病的发病。他们的研究结果为白血病中内源性RNA致癌物获得染色体易位提供了基本的见解。

据悉，肿瘤发生的第一步是获得一系列基因突变来启动和维持恶性肿瘤。急性白血病起始阶段的一个重要例子是，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一个强效致癌基因。

附：英文原文

Title: Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia

Author: Vanessa M. Conn, Marta Gabryelska, John Toubia, Kirsty Kirk, Laura Gantley, Jason A. Powell, Gkhan Cildir, Shashikanth Marri, Ryan Liu, Brett W. Stringer, Scott Townley, Stuart T. Webb, He Lin, Saumya E. Samaraweera, Sheree Bailey, Andrew S. Moore, Mellissa Maybury, Dawei Liu, Alex D. Colella, Timothy Chataway, Craig T. Wallington-Gates, Lucie Walters, Jane Sibbons, Luke A. Selth, Vinay Tergaonkar, Richard J. D’Andrea, Stuart M. Pitson, Gregory J. Goodall, Simon J. Conn

Issue&Volume: 2023-06-08

Abstract: The first step of oncogenesis is the acquisition of a repertoire of genetic mutationsto initiate and sustain the malignancy. An important example of this initiation phasein acute leukemias is the formation of a potent oncogene by chromosomal translocationsbetween 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, alternativelyspliced RNA molecules—are enriched within the MLL recombinome and can bind DNA, formingcircRNA:DNA hybrids (circR loops) at their cognate loci. These circR loops promotetranscriptional pausing, proteasome inhibition, chromatin re-organization, and DNAbreakage. Importantly, overexpressing circRNAs in mouse leukemia xenograft modelsresults 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 insightinto the acquisition of chromosomal translocations by endogenous RNA carcinogens inleukemia.

DOI: 10.1016/j.ccell.2023.05.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00169-1

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