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Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [DRIP-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220271 | GEO | 2024/02/22

REPOSITORIES: GEO

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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.

2024-04-08 | PXD038700 | Pride

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_CMNhuman]

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 associates with intron retention reduction 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. Importantly, histone deacetylase inhibition using vorinostat restored Rloop formation,slowed down DNA replication forks and improved SF3B1-mutated 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.

2024-02-22 | GSE220525 | GEO

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_erythroHuman]

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 associates with intron retention reduction 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. Importantly, histone deacetylase inhibition using vorinostat restored Rloop formation,slowed down DNA replication forks and improved SF3B1-mutated 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.

2024-02-22 | GSE220523 | GEO

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_G1EER]

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 associates with intron retention reduction 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. Importantly, histone deacetylase inhibition using vorinostat restored Rloop formation,slowed down DNA replication forks and improved SF3B1-mutated 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.

2024-02-22 | GSE220516 | GEO

Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Project description:Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in >50% of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of 24 MDS bone marrow samples harboring spliceosome mutations (including hotspot alterations of SF3B1, SRSF2 and U2AF1; small deletions of SRSF2 and truncating mutations of ZRSR2), and devoid of other common co-occurring mutations. We uncover the landscape of splicing alterations in each splice factor mutant MDS and demonstrate that SRSF2 deletions cause highest number of splicing alterations compared with other spliceosome mutations. Although the mis-spliced events observed in different splice factor mutations were largely non-overlapping, a subset of genes, including EZH2, were aberrantly spliced in multiple mutant groups. Pathway analysis revealed that the mis-spliced genes in different mutant groups were enriched in RNA splicing and transport as well as several signaling cascades, suggesting converging biological consequences downstream of distinct spliceosome mutations.

2019-11-07 | GSE128429 | GEO

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

Physiologic expression of Sf3b1K700E causes impaired erythropoieses, aberrant splicing, and sensitivity to pharmacologic spliceosome modulation

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

RNA sequencing of bone marrow CD34+ hematopoietic stem and progenitor cells from patients with myelodysplastic syndrome and healthy controls

Project description:SF3B1, SRSF2 and U2AF1 are the most frequently mutated splicing factor genes in MDS. We have performed a comprehensive analysis to determine the impact of these commonly mutated splicing factors on pre-mRNA splicing in the stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in bone marrow CD34+ cells of a large group of 82 MDS patients. Splicing factor mutations in MDS result in different mechanistic alterations in splicing and largely affect different genes, but these converged in common dysregulated pathways and cellular processes, including RNA splicing, translation and mitochondrial dysfunction, indicating that these mutations operate through common mechanisms in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology and to the phenotypes associated with splicing factor mutations in MDS, whilst several others have not been previously associated with MDS, such as sirtuin signalling.

2018-06-22 | GSE114922 | GEO

Sensitivity of splicing factor mutant hematopoietic cells to GSK-3 inhibition

Project description:Recurrent mutations in the splicing factors SRSF2 and SF3B1 are common in myelodysplasia (MDS) and acute myeloid leukemia (AML). These mutations are invariably heterozygous, as cells with splicing factor mutations nevertheless depend on wild-type splicing activity. Disrupting splicing further is lethal, suggesting a therapeutic vulnerability for splicing factor mutant hematopoietic neoplasms. Glycogen synthase kinase-3 (GSK-3) phosphorylates multiple splicing factors, including SRSF2 and SF3B1, and regulates the splicing of a broad range of mRNAs in human cells. Inhibition of GSK-3 disrupts splicing and promotes cell death in hematopoietic cells with heterozygous mutations in SRSF2 or SF3B1 and not in cells with wild-type splicing factors. To characterize how GSK-3 inhibition alters splicing and leads to cell death in SRSF2P95H/+ and SF3B1K700E/+ cells, we have performed deep RNA sequencing on K562 cells with SRSF2P95H/+ or SF3B1K700E/+ knocked into the endogenous locus (provided by Omar Abdel-Wahab (Wang et al; PMID 30799057) and treated with the GSK-3 inhibitor CHIR99021. Parental cells with wild-type splicing factors were included as controls. RNA-Seq data were further analyzed through the rMATS pipeline to assess changes in mRNA splicing (Liu et al, 2023).

2023-06-28 | GSE235600 | GEO

Novel SF3B1 Deletion Mutations Result in Aberrant RNA Splicing in CLL Patients

Project description:Recurrent mutations in RNA splicing factors SF3B1, U2AF1, and SRSF2 have been reported in hematologic cancers including myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). However, SF3B1 is the only splicing associated gene to be found mutated in CLL and has been shown to induce aberrant splicing. To investigate if any other genomic aberration caused similar transcriptome changes, we clustered RNASeq samples based on an alternative 3’ splice site (ss) pattern previously identified in SF3B1-mutant CLL patients. Out of 215 samples, we identified 37 (17%) with alternative 3’ ss usage, the majority of which harbored known SF3B1 hotspot mutations. Interestingly, 3 patient samples carried previously unreported in-frame deletions in SF3B1 around K700, the most frequent mutation hotspot. To study the functional effects of these deletions, we used various minigenes demonstrating that recognition of canonical 3’ ss and alternative branchsite are required for aberrant splicing, as observed for SF3B1 p.K700E. The common mechanism of action of these deletions and substitutions result in similar sensitivity of primary cells towards splicing inhibitor E7107. Altogether, these data demonstrate that novel SF3B1 in-frame deletion events identified in CLL result in aberrant splicing, a common biomarker in spliceosome-mutant cancers.

2017-06-27 | GSE95352 | GEO

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