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U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations [RNA-Seq]

ABSTRACT: The mechanisms by which mutations of the splicing factor gene U2AF1 contribute to lung adenocarcinoma pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. One specific KRAS mutation, G12S, leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. However, expression of the U2AF1 S34F mutant reverts this exon skipping and restores KRAS function, leading to an enrichment of U2AF1 S34F mutations in KRAS G12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRAS Q61R and U2AF1 I24T mutations. Experimentally, KRAS Q61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1 I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations in a dynamic process of cascading selection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328821 | GEO | 2026/04/29

REPOSITORIES: GEO

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U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

Project description:The mechanisms by which mutations of the splicing factor gene U2AF1 contribute to lung adenocarcinoma pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. One specific KRAS mutation, G12S, leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. However, expression of the U2AF1 S34F mutant reverts this exon skipping and restores KRAS function, leading to an enrichment of U2AF1 S34F mutations in KRAS G12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRAS Q61R and U2AF1 I24T mutations. Experimentally, KRAS Q61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1 I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations in a dynamic process of cascading selection.

2026-04-29 | GSE328804 | GEO

Whole transcriptome splicing analysis in isogenic lung epithelial and adenocarcinoma cell lines with or without a recurrent splicing factor mutation, U2AF1 (S34F)

Project description:The splicing factor gene, U2AF1, is recurrently mutated in a variety of human cancers, including lung adenocarcinomas. The most frequent U2AF1 mutant, U2AF1 p.Ser34Phe (S34F), induces specific changes in pre-mRNA splicing, but it is unclear how these splicing changes are regulated. We have used genomic editing methods to modify the U2AF1 gene locus in an immortalized human bronchial epithelial cell line (HBEC3kt) and in human lung adenocarcinoma cells with pre-existing U2AF1 alleles, creating a U2AF1 S34F allele in the endogenous locus of HBEC3kts and inactivating U2AF1 S34F alleles in two lung adenocarcinoma cell lines (H441 and HCC78). By comparing global splicing alterations in these isogenic pairs of cell lines, we have identified many splicing alterations that are associated with the U2AF1 S34F mutation. Further, by decreasing the levels of wild-type U2AF1 in the isogenic HBEC3kt cells, we show that the magnitude of mutant-associated splicing is proportional to the ratio of S34F:WT gene products. This observation suggest that wild-type U2AF1 is a negative regulator of splicing alterations induced by U2AF1 S34F.

2016-09-30 | GSE80136 | GEO

Nanopore sequencing reveals isoform-specific alterations in human bronchial epithelial cells with U2AF1 S34F mutations

Project description:U2AF1 S34F is one of the most recurrent splicing factor mutations in lung adenocarcinoma (ADC) and has been shown to cause transcriptome-wide pre-mRNA splicing alterations. While U2AF1 S34F-associated splicing alterations have been described, the fate of affected mRNA isoforms remains largely unexplored. To better understand the impact U2AF1 S34F has on isoform fate and function, we conducted high-throughput long-read cDNA sequencing from isogenic human bronchial epithelial cells with and without U2AF1 S34F mutation. We find that nearly 75% (49,366) of our long-read constructed multi-exon isoforms do not overlap GENCODE or short-read assembled isoforms, a large proportion of which (12,397) are due to novel junction connectivity rather than novel splice site usage. We find 198 transcript isoforms with significant expression and usage changes relative to wild-type, some of which were not assembled by short-reads. We find an enrichment of isoforms from immune related genes are down regulated in the presence of U2Af1 S34F, none of which are observed to have splicing changes detected from long-read data. Finally, we reveal that isoforms likely targeted by nonsense-mediated decay are largely downregulated in U2AF1 S34F cells, suggesting that the impact of observed isoform changes may alter the translational output of affected genes. Altogether, our data builds on previous work by providing a higher resolution transcriptome snapshot of full-length isoform alterations associated with U2AF1 S34F in HBEC3kt cells.

2022-06-30 | GSE140734 | GEO

RNA sequencing of erythroid and granulomonocytic colonies differentiated from transduced bone marrow CD34+ cells expressing U2AF1 S34F mutation, U2AF1 wild-type or empty vector control

Project description:Mutations of the splicing factor U2AF1 are frequent in the myeloid malignancy myelodysplastic syndromes (MDS) and in other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and increasing bone marrow blasts. We investigated the impact of the common U2AF1 S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1 S34F expression in human hematopoietic progenitors impairs erythroid differentiation, and skews granulomonocytic differentiation towards granulocytes. RNA-sequencing of erythroid and granulomonocytic colonies revealed that U2AF1 S34F induced a higher number of cassette exon splicing events in granulomonocytic than erythroid cells, and altered mRNA splicing of many transcripts (expressed in both cell types) in a lineage-specific manner. The introduction of isoform changes identified in the target genes H2AFY and STRAP into hematopoietic progenitors recapitulated phenotypes associated with U2AF1 S34F expression in erythroid and/or granulomonocytic cells, suggesting a causal link. Importantly, we provided evidence showing that isoform modulation of the U2AF1 S34F target genes H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1 S34F MDS cells, raising the possibility of using splicing modulators therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity, and for the development of new targeted therapies.

2017-04-25 | GSE94153 | GEO

Identification of differentially spliced genes by wild type or S34F mutation of U2AF1

Project description:Identification of differentially spliced genes by wild type or S34F mutation of U2AF1 Examination of effects on splicing events by overexpressing wipdtype or S34F mutation of two U2AF1 isoforms in A549 cells. All experimental conditions are performed in duplicate.

2015-11-01 | E-GEOD-66553 | biostudies-arrayexpress

U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

Project description:U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

| PRJNA1456563 | ENA

RNA sequencing of common myeloid progenitors following short term induction of mutant U2AF1(S34F) expression in transgenic mice

2015-05-11 | GSE66793 | GEO

RNA sequencing of common myeloid progenitors following short term induction of mutant U2AF1(S34F) expression in transgenic mice

Project description:Mutations in the splicing factor gene U2AF1 have been found in the bone marrow of patients with myelodysplastic syndrome and acute myeloid leukemia, as well as in other cancers. To study the effects of mutant U2AF1(S34F) expression on hematopoiesis and pre-mRNA splicing in hematopoietic cells, we generated two inducible transgenic mouse lines expressing either mutant U2AF1(S34F) or U2AF1(wildtype, WT) as control. We performed strand-specific transcriptome sequencing on bone marrow common myeloid progenitor cells from U2AF1(S34F) and U2AF1(WT)-expressing mice to examine the pre-mRNA splicing changes associated with expression of mutant U2AF1(S34F). Donor-derived common myeloid progenitor cells from mice transplanted with U2AF1(S34F)/rtTA or U2AF1(WT)/rtTA bone marrow were sorted by flow cytometry, and RNA was extracted for transcriptome analysis. Ribosomal RNA was depleted prior to strand-specific RNA sequencing (TruSeq stranded library production, followed by 2 x 100bp paired-end sequencing performed on the HiSeq2000 platform from Illumina). Three samples were sequenced per genotype (n=3), and each sample was composed of bone marrow from 4-5 mice pooled. Reads were aligned to the mouse mm9 reference genome using TopHat (version 2.0.8), and we performed all subsequent analyses in R.

2015-05-11 | E-GEOD-66793 | biostudies-arrayexpress

RNA sequencing of mouse bone marrow cells from transgenic mice following short term induction of mutant U2AF1(S34F) or U2AF1(WT) expression concurrent with sudemycin D6 (or vehicle) treatment in vivo

Project description:Mutations in spliceosome genes occur in the bone marrow of approximately 50% of patients with myelodysplastic syndromes (MDS), with mutations in the splicing factor gene U2AF1 found in ~11% of MDS patients. We hypothesized that cells harboring a spliceosome gene mutation would have increased sensitivity to further perturbation of the spliceosome by splicing modulator drugs. To examine the effects of the splicing modulator drug sudemycin D6 on primary hematopoietic cells expressing mutant U2AF1(S34F), we treated transgenic mice expressing either mutant U2AF1(S34F) or U2AF1(wildtype, WT) concurrently with 5 days of sudemycin D6 treatment in vivo. We harvested bulk bone marrow cells 18 hours after the last day of treatment and performed strand-specific transcriptome sequencing to examine the cumulative pre-mRNA splicing changes associated with both mutant U2AF1 expression and sudemycin D6 treatment.

2016-11-15 | GSE89834 | GEO

Effect of U2AF1-S34F mutation in mouse neutrophils

Project description:To investigate the effect of the MDS-associated U2AF1-S34F mutation on gene expression and pre-mRNA splicing in mouse neutrophils, we performed RNA-seq on RNA isolated from bone marrow neutrophils expressing either U2AF1-S34F or U2AF1-WT transgenes

2024-08-26 | GSE209799 | GEO

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