Erratum: Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

Dolatshad, Hamid; Pellagatti, Andrea; Fernández-Mercado, Marta; Yip, Bon Ham; Malcovati, Luca; Attwood, Martin; Przychodzen, B.; Sahgal, Natasha; Kanapin, Alexander; Lockstone, Helen; Scifo, L; Vandenberghe, Peter; Papaemmanuil, Elli; Smith, Christopher W.; Campbell, P.J.; Ogawa, Shimpei; Maciejewski, Jaroslaw P.; Cazzola, Mario; Savage, Kienan I.; Boultwood, Jacqueline

doi:10.1038/leu.2015.178

Cited by 38 publications

(31 citation statements)

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“…Certain mutations are associated with specific abnormalities in differentiation, such as the formation of ring sideroblasts in cases with SF3B1 mutations and impaired erythropoiesis and hypolobated micromegakaryocytes in patients with 5q − syndrome 54,181 .…”

Section: The Molecular Genetics Of Mdsmentioning

confidence: 99%

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

2016

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Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated hematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal hematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic hematopoietic differentiation, and the absence of features that define acute leukemia. Over 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation, and transcription. In this review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems, and therapeutic approaches.

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Section: The Molecular Genetics Of Mdsmentioning

confidence: 99%

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

2016

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“…46 SF3B1 mutant cell lines were found to have differential expression of genes involved in iron homeostasis and MDS pathogenesis, as well as mitochondrial metabolism and RNA splicing. 47 On the other hand, aberrant splicing of certain kinases in MDS results in hyperactivation of NF-κB signaling pathway, disrupting normal physiological processes in the cells and promoting malignant precursors. 10 An underlying theme in MDS-related spliceosomopathies is the resulting genomic instability.…”

Section: Myelodysplastic Syndromesmentioning

confidence: 99%

Spliceosomopathies: Diseases and mechanisms

Griffin

Saint-Jeannet

2020

Developmental Dynamics

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The spliceosome is a complex of RNA and proteins that function together to identify intron‐exon junctions in precursor messenger‐RNAs, splice out the introns, and join the flanking exons. Mutations in any one of the genes encoding the proteins that make up the spliceosome may result in diseases known as spliceosomopathies. While the spliceosome is active in all cell types, with the majority of the proteins presumably expressed ubiquitously, spliceosomopathies tend to be tissue‐specific as a result of germ line or somatic mutations, with phenotypes affecting primarily the retina in retinitis pigmentosa, hematopoietic lineages in myelodysplastic syndromes, or the craniofacial skeleton in mandibulofacial dysostosis. Here we describe the major spliceosomopathies, review the proposed mechanisms underlying retinitis pigmentosa and myelodysplastic syndromes, and discuss how this knowledge may inform our understanding of craniofacial spliceosomopathies.

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“…Despite this general SF3B1 decreased expression, we carried out RT-PCR experiments to study splicing events specifically altered upon downregulation of SF3B1, in order to evaluate the capacity of SF3B1 wt INS and SF3B1 K700E INS to compensate for the splicing defects caused by SF3B1 depletion. We decided to study specific exon skipping events in RBM5, DUSP11, CCNA2, and STK6, the splicing of which was known to be modified upon either SF3B1 silencing [22,30] or treatment by the spliceosome inhibitor spliceotastin A [31]. Depletion of SF3B1 in siRNA-only transfected cells or in K562 cells co-transfected with the empty vector favored skipping of exon 6 in RBM5, of exon 6 in DUSP11, of exon 5 in CCNA2 and of exons 4-5-6 in STK6 ( Figure 2D,E), as previously described.…”

Section: Insmentioning

confidence: 99%

“…Approximately half of aberrant transcripts are predicted to be degraded by the non-sense mediated mRNA decay (NMD), while the other half would be translated into proteins with potentially altered function [16]. Importantly, the differentially expressed genes and aberrant splicing events observed in cells with disease-related SF3B1 point mutations appear to be different from those observed upon depletion of SF3B1 [22,23], stressing the fact that SF3B1 mutants bear specific functions. Interestingly, Zhang et al recently reported that disease-causing mutations in SF3B1 alter splicing by disrupting interaction with the spliceosomal protein SUGP1 [24], providing a possible mechanistic explanation for the phenotype of SF3B1 point mutants.…”

Section: Introductionmentioning

confidence: 99%

Human Cancer-Associated Mutations of SF3B1 Lead to a Splicing Modification of Its Own RNA

Bergot

Lippert

Douet‐Guilbert

et al. 2020

Cancers

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Deregulation of pre-mRNA splicing is observed in many cancers and hematological malignancies. Genes encoding splicing factors are frequently mutated in myelodysplastic syndromes, in which SF3B1 mutations are the most frequent. SF3B1 is an essential component of the U2 small nuclear ribonucleoprotein particle that interacts with branch point sequences close to the 3’ splice site during pre-mRNA splicing. SF3B1 mutations mostly lead to substitutions at restricted sites in the highly conserved HEAT domain, causing a modification of its function. We found that SF3B1 was aberrantly spliced in various neoplasms carrying an SF3B1 mutation, by exploring publicly available RNA sequencing raw data. We aimed to characterize this novel SF3B1 transcript, which is expected to encode a protein with an insertion of eight amino acids in the H3 repeat of the HEAT domain. We investigated the splicing proficiency of this SF3B1 protein isoform, in association with the most frequent mutation (K700E), through functional complementation assays in two myeloid cell lines stably expressing distinct SF3B1 variants. The yeast Schizosaccharomyces pombe was also used as an alternative model. Insertion of these eight amino acids in wild-type or mutant SF3B1 (K700E) abolished SF3B1 essential function, highlighting the crucial role of the H3 repeat in the splicing function of SF3B1.

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Erratum: Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells

Cited by 38 publications

References 0 publications

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

Spliceosomopathies: Diseases and mechanisms

Human Cancer-Associated Mutations of SF3B1 Lead to a Splicing Modification of Its Own RNA

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