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Transcriptome analysis of SF3B1-mutation induced changes in K562 cells

ABSTRACT: Using RNA-Seq, we determined changes to gene expression and splicing on inducible expression of SF3B1-WT and SF3B1-MUT (K700E) in K562 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70959 | GEO | 2016/07/15

SECONDARY ACCESSION(S): PRJNA290019

REPOSITORIES: GEO

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Transcriptome analysis of SF3B1-mutation induced changes in K562 cells

Project description:Using RNA-Seq, we determined changes to gene expression and splicing on inducible expression of SF3B1-WT and SF3B1-MUT (K700E) in K562 cells. Using RNA-Seq, we determined changes to gene expression and splicing on inducible expression of SF3B1-WT and SF3B1-MUT (K700E) in K562 cells.

2016-07-15 | E-GEOD-70959 | biostudies-arrayexpress

Cancer-associated SF3B1-K700E mutation controls immune responses by regulating Treg function via aberrant Anapc13 splicing

Project description:Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic cell-derived malignancies, with SF3B1-K700E being the most common one. Here we show that Treg specific expression of SF3B1-K700E (Sf3b1K700Efl/+/Foxp3YFP-Cre) results in spontaneous autoimmune phenotypes including enlarged spleen and tissue infiltration with IFN-γ-producing CD4+ T cells. CD4+ T cells from Sf3b1K700Efl/+/Foxp3YFP-Cre mice display defective Treg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs. Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator Anapc13 due to insertion a 231 bp DNA fragment to the 5’ untranslated region (UTR). Forced expression of Anapc13 gene restores the differentiation and ability of Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs to prevent adoptive transfer colitis. Our results thus highlight the impact of a hematological malignancy-associated SF3B1 mutation on immune responses and indicate a potential relationship between splicing factor mutation-dysregulated immune responses and cancer development.

2024-06-01 | GSE267436 | GEO

Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs

Project description:SF3B1 K700E is the most frequent mutation in myelodysplastic syndrome (MDS), but the mechanisms by which it drives MDS pathogenesis remain unclear. We derived a panel of 18 genetically matched SF3B1 K700E- and SF3B1 WT-induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1 K700E mutations and performed RNA and ATAC sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from them. We developed a novel computational framework integrating splicing with transcript usage and gene expression analyses and derived a SF3B1 K700E splicing signature consisting of 59 splicing events linked to 34 genes, which associates with the SF3B1 mutational status of primary MDS patient cells. The chromatin landscape of SF3B1 K700E HSPCs showed increased priming toward the megakaryocyte- erythroid lineage. Transcription factor motifs enriched in chromatin regions more accessible in SF3B1 K700E cells included, unexpectedly, motifs of the TEAD family. TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1 K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1 K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.

2022-03-08 | GSE184246 | GEO

Chronic Lymphocytic Leukemia MEC1 SF3B1 K700E and Wild Type Cell Lines' RNA-seq after Treatment with H3B-8800 Splicing Modulator.

Project description:To study the impact of SF3B1 mutations on alternative splicing and the effect of H3B-8800 splicing modulator in wild type and SF3B1-mutant chronic lymphocytic leukemia cells, we established SF3B1 K700E MEC1 CLL isogenic cell line and carried out RNA deep sequencing in SF3B1 wild type and K700E MEC1 cell lines upon H3B-8800 treatment.

2023-08-08 | GSE190087 | GEO

Long-read sequencing of CLL and MDS patients uncovers molecular effects of SF3B1 mutations in cancer (SF3B1 & U2AF2 iCLIP)

Project description:Alternative splicing plays a critical role in generating transcriptome diversity, and aberrant splicing is frequently observed in cancer. Mutations in the splicing factor SF3B1 are particularly common in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS), with different survival prognoses. We applied long-read sequencing for the investigation of the SF3B1 mutation effect on the transcriptome of MDS and CLL patients, as well as isogenic cell lines. Our results revealed that SF3B1 mutation effect was common across the different diseases and specifically altered the usage of 3’ alternative splice sites within short proximity to the canonical splice sites. Based on computational simulations, the most common K700E mutation led to destabilization of the SF3B1-mRNA binding. Furthermore, we combined the full isoform information with genome-wide SF3B1-RNA binding maps to predict the functional consequences of the aberrant splicing and gain mechanistic insights into the role of mutated SF3B1 in splicing.

2024-08-19 | GSE247658 | GEO

Transcriptome analysis of chronic lymphoid leukemia reveals isoform regulation associated with mutations in SF3B1

Project description:Several DNA sequencing studies of chronic lymphocytic leukemia (CLL) revealed that the splicing factor SF3B1 accumulated somatic point mutations in about 10 percent of the patients. In most cases the mutations were located in the genomic regions coding for the C-terminal HEAT-repeat domain and in many cases, the mutations gave rise to specific amino acid substitutions. Here, we aimed to investigate differential usage of exons associated with the mutation K700E of SF3B1 in CLL tumuor cells. We generated RNA-Seq transcriptome data from two patients with mutations in SF3B1, two patient without mutations in SF3B1 and from healthy donors. We report interesting examples and possible consequences of the alternative exon usage in these genes. This dataset contains only the files resulting from the processing the RNA sequencing raw data. This avoids potential patient identifiability, but ensures the full reproducibility of the results described in the publication.

2013-12-27 | E-MTAB-2025 | biostudies-arrayexpress

RNA-Seq of human K-562 leukaemia cell line with and without K700E mutation in coding region of SF3B1 gene

Project description:The aim of this experiment was to compare the transcriptomes of SF3B1 mutant and wildtype isogenic cells at the whole cell, nuclear and cytoplasmic levels. Mutations in SF3B1 are often found in the malignant cells of patients suffering from myelodysplastic syndromes and more rarely in other cancer types. The human K-562 leukaemia cell line was modified using CRISPR/Cas9 to integrate an A>G mutation in the SF3B1 consensus coding sequence to change the 700th codon from lysine to glutamic acid (K700E). RNA-Seq was ribo-depleted and randomly primed using SMARTer® Stranded Total RNA Sample Prep Kit. Sequencing used an Illumina NextSeq.

2019-02-25 | E-MTAB-7192 | biostudies-arrayexpress

Cancer-associated SF3B1 Mutations Inhibit mRNA Nuclear Export by Disrupting SF3B1–THOC5 Interactions

Project description:Pre-mRNA splicing and nuclear export are coordinated processes that ensure efficient and accurate gene expression. In recent years, disruptions in this process have been found to result in substantial gene expression aberrations, with potential contributions from SF3B1 mutations, whose mechanism remains elusive. The present study reveals that the K700E mutation in SF3B1 attenuates its interaction with THOC5, resulting in reduced mRNA binding by THOC5, and ultimately, the inhibition of mRNA nuclear export. Interestingly, overexpressing THOC5 can restore the attenuated interaction, facilitating mRNA nuclear export. Importantly, other cancer-associated SF3B1 mutations may exert a similar impact. Our research highlights the critical role of the THOC5–SF3B1 interaction in regulating mRNA nuclear export and provides valuable insights into the impact of SF3B1 mutations on this process.

2024-09-12 | GSE268355 | GEO

RNA-seq of human K562 leukemia cells with or without a mutation in SF3B1 (splicing factor 3b, subunit 1) that were treated with DMSO or the STAT3 inhibitor STATTIC

Project description:The purpose of the experiment was to define the gene expression and splicing alterations occurring when human wildtype or splicing factor 3b subunit 1 (SF3B1) mutant K562 cells had STAT3 inhibited with the small molecule STATTIC. Results provide insight the interplay of SF3B1 and STAT3 in human hematopoietic cells.

2022-12-13 | GSE206020 | GEO

Engineering oncogenic hotspot mutations on SF3B1 via CRISPR-directed PRECIS mutagenesis

Project description:To engineer novel SF3B1 mutant cell lines, we developed a methodology called PRECIS to install the pathogenic K700E mutation. We used this method to engineer CLL cell lines HG-3 and MEC-1 with the SF3B1 K700E mutation and then carried out RNA-seq.

2024-08-28 | GSE231387 | GEO

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