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U2AF1 S34F enhances tumorigenic potential by exhibiting synergy with KRAS mutation and altering response to environmental perturbations

ABSTRACT: U2AF1 S34F, a somatic splicing factor mutation, is frequently recurrent in human neoplasias such as lung adenocarcinoma (ADC). Although U2AF1 S34F has been shown to occur early in tumor lineages, the mutation, alone, is insufficient for producing tumors. However, lung ADC patients with U2AF1 S34F frequently have co-occurring KRAS mutations and smoking histories. We hypothesized that U2AF1 S34F interacts with oncogenic KRAS and environmental stress to promote tumor-forming potential. To elucidate interaction of U2AF1 S34F with a co-occurring mutation, we generated human bronchial epithelial cells (HBEC3kts) with U2AF1 S34F or with co-occurring U2AF1 S34F and KRAS G12V. From analyzing short-read transcriptome sequences, we found synergistic effects of co-occurring mutations on gene expression in cell cycle and inflammatory pathways associated with increased tumors in mouse xenografts, anchorage-independent growth, proliferation, and altered cytokine production. Interestingly, HBEC3kts harboring only U2AF1 S34F display increased splicing in stress granule protein genesand increased viability in cigarette smoke concentrate. Our results suggest that U2AF1 S34F may prime cells for transformation by allowing precancerous cells to survive longer when environmental stress is present, permitting U2AF1 S34F cells to accumulate transforming mutations, such as KRAS G12V

ORGANISM(S): Homo sapiens

PROVIDER: GSE267349 | GEO | 2026/09/30

REPOSITORIES: GEO

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	GSE267349_RAW.tar	Raw
	GSE267349_nonredundant_JuncBase_wt_laczvsS34fkv12_PSI.tsv.gz	Tabular
	GSE267349_nonredundant_JuncBase_wt_laczvsS34flacz_PSI.tsv.gz	Tabular
	GSE267349_nonredundant_JuncBase_wt_laczvswtkv12_PSI.tsv.gz	Tabular

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

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.

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U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations

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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.

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RNA-Seq data from U2 small nuclear RNA auxiliary factor 1 (U2AF1)-S34F and WT SKM-1 cells

Project description:Mutations in the U2 small nuclear RNA auxiliary factor 1 (U2AF1) gene are the common feature of a major subset in myelodysplastic syndromes (MDS). However, the genetic landscape and molecular pathogenesis of oncogenic U2AF1 S34F mutation in MDS are not totally understood. To understand how the cancer-associated U2AF1 S34F mutation promotes MDS, we next compared independent RNA samples of SKM-1 cells expressing wild-type U2AF1 and S34F mutant U2AF1 using RNA-sequencing (RNA-seq).Differentially expressed genes (DEGs) and significantly enriched pathways were identified by RNA-seq.

2021-03-13 | GSE166798 | 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 mutation causes an oxidative stress and DNA repair defect in hematopoietic and leukemic cells

Project description:U2AF1 is a core component of spliceosome and controls cell-fate specific alternative splicing. U2AF1 mutations have been frequently identified in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients, and mutations in U2AF1 are associated with poor prognosis in hematopoietic malignant diseases. To investigate the effects of U2af1 S34F in hematopoietic cells, we performed global gene expression profiling by RNA sequencing on U2af1-WT and U2af1 S34F 32D cells. We find that U2AF1 S34F causes increased reactive oxygen species (ROS) production. In hematopoietic cell line, a defect in mitochondrial function and DNA damage response deficiency are found in U2AF1 S34F expressing 32D cells.

2025-12-01 | GSE282085 | 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

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 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

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