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Expression data from Sf3b1 heterozygous Lineage-c-Kit+Sca-1+ (LSK) bone marrow cells

ABSTRACT: Recent studies have shown that multiple components of the mRNA splicing machinery are mutated in myelodysplastic syndrome (MDS) patients. SF3B1 is frequently mutated in refractory anemia with ringed sideroblasts (RARS)-MDS patients, however, the pathophysiological role of SF3B1 mutations has not been elucidated yet. In this study, we examined the function of Sf3b1 in murine hematopoiesis. Since Sf3b1 null homozygotes died during preimplantation development, in this study, we utilized Sf3b1 heterozygous mice showing grossly normal growth. We harvested bone marrow stem/progenitor (LSK) cells from wild type (WT) and Sf3b1+/- mice (n=4) at 20 weeks old. In addition, to exclude the possibility of indirect effect from bone marrow environment, we transplanted total bone marrow cells from WT or Sf3b1+/- (CD45.2+) mice into lethally irradiated CD45.1+ recipient mice, and then harvested (CD45.2+) LSK cells from the recipients (n=5) at 9 months-post transplantation.

ORGANISM(S): Mus musculus

SUBMITTER: Goro Sashida

PROVIDER: E-GEOD-51038 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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

EIF2AK1-mediated signaling drives SF3B1 mutation-induced arrest in terminal erythroid differentiation in myelodysplastic syndrome with ringed sideroblasts

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A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome (RNA-Seq)

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

Expression data from Sf3b1 heterozygous Lineage-c-Kit+Sca-1+ (LSK) bone marrow cells

Project description:Recent studies have shown that multiple components of the mRNA splicing machinery are mutated in myelodysplastic syndrome (MDS) patients. SF3B1 is frequently mutated in refractory anemia with ringed sideroblasts (RARS)-MDS patients, however, the pathophysiological role of SF3B1 mutations has not been elucidated yet. In this study, we examined the function of Sf3b1 in murine hematopoiesis.

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Expression data from RUNX1S291fs-mutant and/or Ezh2 conditional knockout Lineage-c-Kit+Sca-1+ (LSK) cells

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2013-09-04 | E-GEOD-50537 | biostudies-arrayexpress

Differential gene expression and exon usage in bone marrow from RARS patients with SF3B1 somatic mutations compared to healthy patients.

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

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

2014-11-22 | GSE63569 | GEO

Differential gene expression and exon usage in bone marrow from RARS patients with SF3B1 somatic mutations compared to healthy patients.

2013-01-18 | GSE43603 | GEO

Targeting the EIF2AK1 signaling pathway rescues red blood cell production in SF3B1-mutant myelodysplastic syndromes with ringed sideroblasts

Project description:SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples (MDS-RS-3-bis, MDS-RS-13, and MDS-RS-14), we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production. MACS-purified CD34+ cells were subjected to a 3-phase in vitro culture as described previously (Huang et al., 2020a). Cells were maintained in phase 1 from the day of collection until day 8, at which time the cells underwent ribonucleoprotein-based gene editing and were transitioned to phase 2 medium. On day 13 of culture, the cells were transitioned to phase 3 medium. Samples for Western blot and cytospin analyses, and sample for flow cytometry were harvested on day 13 or 15 of culture, respectively.

2022-07-19 | GSE202722 | GEO

DNA Replication Stress Due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation

Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which tightly associates with reduced retention of introns specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation, which were recapitulated in murine Sf3b1K700E/+ proerythroblasts. Importantly, R-loop formation was restored by histone deacetylase inhibition using SAHA/vorinostat, which improved Sf3b1K700E/+ erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1- mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.

2024-05-29 | PXD038656 | Pride

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