Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells Journal Article


Authors: North, K.; Benbarche, S.; Liu, B.; Pangallo, J.; Chen, S.; Stahl, M.; Bewersdorf, J. P.; Stanley, R. F.; Erickson, C.; Cho, H.; Pineda, J. M. B.; Thomas, J. D.; Polaski, J. T.; Belleville, A. E.; Gabel, A. M.; Udy, D. B.; Humbert, O.; Kiem, H. P.; Abdel-Wahab, O.; Bradley, R. K.
Article Title: Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells
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. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: leukemia; genetics; mutation; mouse; animal; cytology; metabolism; animals; mice; melanoma; breast cancer; gene expression; intron; introns; breast neoplasms; oncology; rna; tumors; breast tumor; gene therapy; thymidine kinase; antivirus agent; uvea tumor; uveal neoplasms; dermatology; ganciclovir; diseases; cancer cells; rna splicing; antiviral agents; viruses; uveal melanoma; procedures; splicing factors; herpes simplex virus thymidine kinase; genetic therapy; humans; human; female; rna splicing factor; rna splicing factors; genes expression; recurrent change; wild-type cells
Journal Title: Nature Biotechnology
Volume: 40
Issue: 7
ISSN: 1087-0156
Publisher: Nature Publishing Group  
Date Published: 2022-07-01
Start Page: 1103
End Page: 1113
Language: English
DOI: 10.1038/s41587-022-01224-2
PUBMED: 35241838
PROVIDER: scopus
PMCID: PMC9288984
DOI/URL:
Notes: Article -- Export Date: 1 August 2022 -- Source: Scopus
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MSK Authors
  1. Hana Cho
    18 Cho
  2. Bo Liu
    19 Liu
  3. Maximilian Stahl
    32 Stahl
  4. Sisi Chen
    6 Chen