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Series GSE163217

Query DataSets for GSE163217

Status

Public on Dec 30, 2021

Title

Synthetic introns enable mutation-dependent targeting of cancer cells

Organism

Experiment type

Other

Summary

Many cancers carry recurrent change-of-function mutations in RNA splicing factor genes, which induce sequence-specific changes in RNA splicing. Here, we describe a method to harness this change in RNA splicing activity to drive splicing factor mutation-dependent gene expression in cancers and selectively eliminate these tumors. We engineered synthetic introns which were efficiently spliced in leukemia and breast epithelial cells bearing the most common SF3B1 mutations, but unspliced in wild-type cells—and vice versa—to yield mutation-dependent protein production. A massively parallel screen of 8,881 distinct introns delineated ideal intronic size, mapped essential sequence elements, and revealed the basis of mutation-dependent splicing. Synthetic introns enabled mutation-dependent expression of herpes simplex virus thymidine kinase and subsequent ganciclovir-mediated elimination of leukemia and breast epithelial cells bearing SF3B1 mutations, while leaving wild-type cells unaffected. This approach significantly decreased the growth of otherwise lethal leukemia xenografts and correspondingly improved host survival. The modular, compact, and specific nature of synthetic introns thereby provide a means to exploit cancer-specific changes in RNA splicing for genotype-dependent gene expression and gene therapy.

Overall design

Analysis of synthetic intron splicing in SF3B1 MUT vs SF3B1 WT cells

Contributor(s)

North KD, Benbarche S, Abdel-Wahab O, Bradley RK

Citation(s)

Submission date

Dec 14, 2020

Last update date

Apr 01, 2022

Contact name

Khrystyna Dilai North

E-mail(s)

Organization name

Fred Hutchinson Cancer Research Center

Department

Basic Sciences Division

Lab

R. Bradley

Street address

1100 Fairview Ave N

City

Seattle

State/province

WA

ZIP/Postal code

98102

Country

USA

Platforms (1)

Illumina MiSeq (Homo sapiens)

Samples (28)

More...

GSM4975208	ELG_K662 Cells SF3B1 K700E_Mini Library_Day 6 GCV (150bp)
GSM4975209	RLG_K662 Cells SF3B1 WT_Mini Library_Day 6 GCV (150bp)
GSM4975210	EL_K662 Cells SF3B1 K700E_Mini Library_Day 6 (150bp)

GSM4975211	PL_K662 Cells SF3B1 WT_Mini Library_Day 6 (150bp)
GSM5017765	s2-E8G-1-150 K562 Cells SF3B1 K700E -- Library -- Day 8 GCV (150bp reads)
GSM5017766	s2-E8G-2-150 K562 Cells SF3B1 K700E -- Library -- Day 8 GCV (150bp reads)
GSM5017767	s2-E8G-3-150 K562 Cells SF3B1 K700E -- Library -- Day 8 GCV (150bp reads)
GSM5017768	s2-P8G-1-150 K562 Cells SF3B1 WT -- Library -- Day 8 GCV (150bp reads)
GSM5017769	s2-P8G-2-150 K562 Cells SF3B1 WT -- Library -- Day 8 GCV (150bp reads)
GSM5017770	s2-P8G-3-150 K562 Cells SF3B1 WT -- Library -- Day 8 GCV (150bp reads)
GSM5017771	s2-E8G-1-250 K562 Cells SF3B1 K700E -- Library -- Day 8 GCV (250bp reads)
GSM5017772	s2-E8G-2-250 K562 Cells SF3B1 K700E -- Library -- Day 8 GCV (250bp reads)
GSM5017773	s2-E8G-3-250 K562 Cells SF3B1 K700E -- Library -- Day 8 GCV (250bp reads)
GSM5017774	s2-P8G-1-250 K562 Cells SF3B1 WT -- Library -- Day 8 GCV (250bp reads)
GSM5017775	s2-P8G-2-250 K562 Cells SF3B1 WT -- Library -- Day 8 GCV (250bp reads)
GSM5017776	s2-P8G-3-250 K562 Cells SF3B1 WT -- Library -- Day 8 GCV (250bp reads)
GSM5017777	s2-E0-1-150 K562 Cells SF3B1 K700E -- Library -- Day 0 (150bp reads)
GSM5017778	s2-E0-2-150 K562 Cells SF3B1 K700E -- Library -- Day 0 (150bp reads)
GSM5017779	s2-E0-3-150 K562 Cells SF3B1 K700E -- Library -- Day 0 (150bp reads)
GSM5017780	s2-P0-1-150 K562 Cells SF3B1 WT -- Library -- Day 0 (150bp reads)
GSM5017781	s2-P0-2-150 K562 Cells SF3B1 WT -- Library -- Day 0 (150bp reads)
GSM5017782	s2-P0-3-150 K562 Cells SF3B1 WT -- Library -- Day 0 (150bp reads)
GSM5017783	s2-E0-1-250 K562 Cells SF3B1 K700E -- Library -- Day 0 (250bp reads)
GSM5017784	s2-E0-2-250 K562 Cells SF3B1 K700E -- Library -- Day 0 (250bp reads)
GSM5017785	s2-E0-3-250 K562 Cells SF3B1 K700E -- Library -- Day 0 (250bp reads)
GSM5017786	s2-P0-1-250 K562 Cells SF3B1 WT -- Library -- Day 0 (250bp reads)
GSM5017787	s2-P0-2-250 K562 Cells SF3B1 WT -- Library -- Day 0 (250bp reads)
GSM5017788	s2-P0-3-250 K562 Cells SF3B1 WT -- Library -- Day 0 (250bp reads)

Relations

BioProject

SRA

Download family	Format
SOFT formatted family file(s)	SOFT
MINiML formatted family file(s)	MINiML
Series Matrix File(s)	TXT

Supplementary file	Size	Download	File type/resource
GSE163217_all_filtered_counts_q1_new.csv.gz	594.6 Kb	(ftp)(http)	CSV
GSE163217_pilot_filtered_counts_q1.csv.gz	425 b	(ftp)(http)	CSV
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Raw data are available in SRA
Processed data are available on Series record

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