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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

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

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

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

Cancer-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1

Project description:SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is the sole defect of mutant SF3B1 spliceosomes and, since this defect can be rescued, suggests possibilities for therapeutic intervention.

2019-07-24 | GSE128805 | GEO

Functional and conformational impact of cancer-associated SF3B1 mutations depends on the position and the charge of amino acid substitution

Project description:RNA-sequencing data from HEK293T cell models: Hek293T transfected with expression vectors of SF3B1-WT, SF3B1-R625H, SF3B1-K666T, SF3B1-K700E.

2021-02-18 | GSE167001 | GEO

RNA-seq of sorted KPC Sf3b1-K700E murine PDAC cells

Project description:We established a mouse model of KrasG12D, Trp53-/- and Sf3b1-K700E murine pancreatic cancer to elucidate the impact of the SF3B1 mutation found in human PDAC on the KPC mouse model.

2022-06-07 | GSE203339 | GEO

RNA sequencing of bone marrow CD34+ cells from myelodysplastic syndrome patients with and without SF3B1 mutation and from healthy controls

Project description:The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34+ cells from MDS patients with SF3B1 mutations using RNA-sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared to wildtype cases include genes involved in MDS pathogenesis (ASXL1, CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7, SLC25A37) and RNA splicing/processing (PRPF8, HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. Our data indicate that SF3B1 plays a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link. RNA-Seq was performed to compare the transcriptome of bone marrow CD34+ cells from eight MDS patients with SF3B1 mutation, four MDS patients with no known splicing mutation and five healthy controls.

2014-11-22 | E-GEOD-63569 | biostudies-arrayexpress

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