EGAS00001000089-sc-20111014 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001000045 | EGA |
REPOSITORIES: EGA
Publications
Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts.
Papaemmanuil E E Cazzola M M Boultwood J J Malcovati L L Vyas P P Bowen D D Pellagatti A A Wainscoat J S JS Hellstrom-Lindberg E E Gambacorti-Passerini C C Godfrey A L AL Rapado I I Cvejic A A Rance R R McGee C C Ellis P P Mudie L J LJ Stephens P J PJ McLaren S S Massie C E CE Tarpey P S PS Varela I I Nik-Zainal S S Davies H R HR Shlien A A Jones D D Raine K K Hinton J J Butler A P AP Teague J W JW Baxter E J EJ Score J J Galli A A Della Porta M G MG Travaglino E E Groves M M Tauro S S Munshi N C NC Anderson K C KC El-Naggar A A Fischer A A Mustonen V V Warren A J AJ Cross N C P NC Green A R AR Futreal P A PA Stratton M R MR Campbell P J PJ
The New England journal of medicine 20110926 15
<h4>Background</h4>Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies.<h4>Methods</h4>We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), ...[more]
Similar Datasets
Project description:SF3B1, splicing factor 3b subunit 1 is a component of the RNA splicing machinery and it has been found to be highly mutated in refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T). The aim of this study is to investigate the RNA splicing patterns in bone marrow from patients with SF3B1 somatic mutations compared to normal physiologic splicing. We compared the RNA splicing pattern as exon usage, differential gene expression, and pathway analysis with normal splicing mRNA profiles, as measured by RNA-Seq, in bone marrow derived mononuclear cells from 2 RARS patients with SF3B1 somatic mutations were compared to the mRNA profile of a normal donor.
2013-01-18 | E-GEOD-43603 | biostudies-arrayexpress
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
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
Project description:SIFD (Congenital sideroblastic anemia, B-cell immunodeficiency, Periodic fevers and Developmental delay) Syndrome is caused by biallelic mutations in tRNA nucleotidyltransferase CCA-adding, 1 (TRNT1) gene. The onset of the disease is usually neonatal or in early infancy and the clinical presentation is widely heterogeneous. Myelodysplastic syndromes (MDS) with ring sideroblasts, which is characterised by somatic mutations in SF3B1 gene in more than 80% of cases, have never been reported as associated with SIFD Syndrome. Here we report a case of an adult male patient with a novel non-sense heterozygous mutation in TRNT1 gene, which developed MDS with somatic K700E SF3B1 mutation and trisomy 8. WES revealed additional somatic variations affecting genes implicated in cell proliferation, apoptosis and DNA mismatch repair: ARID1A, HERC1, IL4R, TMEM260 and CDKL3. Besides the typical recurrent aseptic pneumonias and sinopulmonary bacterial infections, he developed lymphohistiocytic subcutaneous panniculitis and subsequently a subcutaneous panniculitis-like T-cell lymphoma (SPTCL), suggesting that predisposition in the TRNT1 positive syndrome extends to both lymphoid and myeloid neoplasms. This report is particularly relevant to provide insights on the hematological impact of TRNT1 positive syndrome in adults and to improve early diagnosis and management of this rare disease.
2020-09-14 | GSE120007 | GEO
Project description:SF3B1, splicing factor 3b subunit 1 is a component of the RNA splicing machinery and it has been found to be highly mutated in refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T). The aim of this study is to investigate the RNA splicing patterns in bone marrow from patients with SF3B1 somatic mutations compared to normal physiologic splicing. We compared the RNA splicing pattern as exon usage, differential gene expression, and pathway analysis with normal splicing
2013-01-18 | GSE43603 | GEO
Project description:Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem celldisorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. MDS patientswith SF3B1 mutations often accumulate excessive tissue iron, even in the absence oftransfusions, but the mechanisms that are responsible for their parenchymal iron overload areunknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis arecontrolled by the hormone hepcidin, which is regulated by erythroblasts through secretion of theerythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript inMDS patients with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity tosuppress hepcidin transcription. Plasma concentrations of ERFE were higher in MDS patientswith a SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidinsuppression by a variant erythroferrone is likely responsible for the increased iron loading inpatients with SF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent ironmediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variantERFE as a specific biomarker of clonal erythropoiesis.
2019-06-18 | GSE132836 | GEO
Project description:Over 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knock-in mouse model of the most common SF3B1 mutation, Sf3b1K700E. Sf3b1K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills Sf3b1K700E-expressing cells. Thus, Sf3b1K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.
2016-08-17 | GSE85712 | GEO
Project description:Hotspot mutations in the spliceosomal component gene SF3B1 underpin a number of cancers and have a neomorphic function leading to global disruption of canonical splicing and aberrant splicing of hundreds of transcripts. However, the functional consequences of this misplicing and resultant genetic vulnerabilities imposed by these events are poorly understood. Through a synthetic-lethal approach we identify that SF3B1 mutant cells are selectively sensitive to PARP inhibitors. This vulnerability is preserved across multiple cell line and patent derived tumour models, independent of SF3B1 hotspot mutation and is manifested both in vitro and in vivo. These data provide the pre-clinical and mechanistic rationale for assessing SF3B1 mutations as a biomarker of single-agent PARP inhibitor response in a new patient population and may extend the clinical utility of these agents beyond BRCA mutated cancers.
2023-04-19 | PXD019046 | Pride
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
Project description:RNA splicing factor SF3B1 is recurrently mutated in various cancers, particularly in hematological malig-nancies. We previously reported that co-expression of Sf3b1 mutation and Atm deletion in B cells, but not either lesion alone, leads to the onset of chronic lymphocytic leukemia (CLL) with CLL cells harboring chromosome amplification. However, the exact role of Sf3b1 mutation and Atm deletion in chromosomal instability (CIN) remains unclear. Here, we demonstrate that SF3B1 mutation promotes centromeric R-loop (cen-R-loop) accumulation, leading to increased chromosome oscillation, impaired chromosome segrega-tion, altered spindle architecture and aneuploidy, which can be alleviated by removal of cen-R-loop and exaggerated by deletion of ATM. Aberrant splicing of key genes involved in R-loop processing underlies augmentation of cen-R-loop as overexpression of the normal isoform, but not the altered form, mitigates mitotic stress in SF3B1 mutant cells. Our study underscores the critical role of novel splice variants in link-ing RNA splicing dysregulation and CIN, and highlights cen-R-loop augmentation as a key mechanism for leukemogenesis.
2023-09-06 | GSE235208 | GEO