美国华盛顿大学Robert K. Bradley、纪念斯隆•凯特琳癌症中心Omar Abdel-Wahab等研究人员合作发现,合成内含子实现对癌细胞的剪接因子突变依赖性靶向。该研究于2022年3月3日在线发表于国际一流学术期刊《自然—生物技术》。
Title: Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells
Author: North, Khrystyna, Benbarche, Salima, Liu, Bo, Pangallo, Joseph, Chen, Sisi, Stahl, Maximilian, Bewersdorf, Jan Philipp, Stanley, Robert F., Erickson, Caroline, Cho, Hana, Pineda, Jose Mario Bello, Thomas, James D., Polaski, Jacob T., Belleville, Andrea E., Gabel, Austin M., Udy, Dylan B., Humbert, Olivier, Kiem, Hans-Peter, Abdel-Wahab, Omar, Bradley, Robert K.
Issue&Volume: 2022-03-03
Abstract: Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors. Here, we describe a method to harness this abnormal splicing activity to drive splicing factor mutation-dependent gene expression to selectively eliminate tumor cells. We engineered synthetic introns that were efficiently spliced in cancer cells bearing SF3B1 mutations, but unspliced in otherwise isogenic wild-type cells, to yield mutation-dependent protein production. A massively parallel screen of 8,878 introns delineated ideal intronic size and mapped elements underlying mutation-dependent splicing. Synthetic introns enabled mutation-dependent expression of herpes simplex virus–thymidine kinase (HSV–TK) and subsequent ganciclovir (GCV)-mediated killing of SF3B1-mutant leukemia, breast cancer, uveal melanoma and pancreatic cancer cells in vitro, while leaving wild-type cells unaffected. Delivery of synthetic intron-containing HSV–TK constructs to leukemia, breast cancer and uveal melanoma cells and GCV treatment in vivo significantly suppressed the growth of these otherwise lethal xenografts and improved mouse host survival. Synthetic introns provide a means to exploit tumor-specific changes in RNA splicing for cancer gene therapy.
DOI: 10.1038/s41587-022-01224-2
Source: https://www.nature.com/articles/s41587-022-01224-2
Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex
本期文章:《自然—生物技术》:Online/在线发表