SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

Visconte, Valeria; Rogers, Heesun J.; Singh, Jarnail; Barnard, John; Bupathi, Manoj; Traina, Fabı́ola; McMahon, James T.; Makishima, Hideki; Szpurka, Hadrian; Jankowska, Anna; Jerez, Andrés; Sekeres, Mikkael A.; Saunthararajah, Yogen; Advani, Anjali S.; Copelan, Edward A.; Koseki, Haruhiko; Isono, Kyoichi; Padgett, Richard A.; Osman, Sami; Koide, Kazunori; O’Keefe, Christine L.; Maciejewski, Jaroslaw P.; Tiu, Ramon V.

doi:10.1182/blood-2012-05-430876

Cited by 169 publications

(142 citation statements)

References 32 publications

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“…Thus, SF3a, SF3b, and Eftud2 all are required for retention of exon 2 in MyD88, as this exon is lost and MyD88 S is produced when any of these spliceosome components are inhibited. This result is consistent with other reports that show that inhibition of specific spliceosome subunits leads to alternative splicing and exon skipping (Corrionero et al 2011;Fan et al 2011;An and Henion 2012;Visconte et al 2012). Moreover, the current data show that regulators of the U2 snRNP (SF3a and SF3b), which affect 39 splice site choice, and the U5 snRNP (Eftud2), which joins the spliceosome at a later stage of assembly (Newman 1997;Turner et al 2004;Wahl et al 2009), both have similar effects on MyD88 mRNA splicing.…”

Section: The Role Of Atp6v1c1 In Innate Immunity Regulationsupporting

confidence: 82%

Comparative Genomics RNAi Screen Identifies Eftud2 as a Novel Regulator of Innate Immunity

et al. 2014

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The extent of the innate immune response is regulated by many positively and negatively acting signaling proteins. This allows for proper activation of innate immunity to fight infection while ensuring that the response is limited to prevent unwanted complications. Thus mutations in innate immune regulators can lead to immune dysfunction or to inflammatory diseases such as arthritis or atherosclerosis. To identify novel innate immune regulators that could affect infectious or inflammatory disease, we have taken a comparative genomics RNAi screening approach in which we inhibit orthologous genes in the nematode Caenorhabditis elegans and murine macrophages, expecting that genes with evolutionarily conserved function also will regulate innate immunity in humans. Here we report the results of an RNAi screen of approximately half of the C. elegans genome, which led to the identification of many candidate genes that regulate innate immunity in C. elegans and mouse macrophages. One of these novel conserved regulators of innate immunity is the mRNA splicing regulator Eftud2, which we show controls the alternate splicing of the MyD88 innate immunity signaling adaptor to modulate the extent of the innate immune response.

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Section: The Role Of Atp6v1c1 In Innate Immunity Regulationsupporting

confidence: 82%

Comparative Genomics RNAi Screen Identifies Eftud2 as a Novel Regulator of Innate Immunity

et al. 2014

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“…The most highly mutated SF3B1 position in MDS and other cancers, K700, resides within a loop that connects two α helices at HEAT repeat 7 (Quesada et al 2012;Visconte et al 2012). Recently, it was reported that the U2 snRNP SF3B complex has conformational changes from a closed stage to an open stage to allow interactions with other spliceosomal components and the BS (Golas et al 2003).…”

Section: The Meaning Of Mutations and Changes In Bs Fidelitymentioning

confidence: 99%

SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

et al. 2016

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Mutations in the U2 snRNP component SF3B1 are prominent in myelodysplastic syndromes (MDSs) and other cancers and have been shown recently to alter branch site (BS) or 3 ′ splice site selection in splicing. However, the molecular mechanism of altered splicing is not known. We show here that hsh155 mutant alleles in Saccharomyces cerevisiae, counterparts of SF3B1 mutations frequently found in cancers, specifically change splicing of suboptimal BS pre-mRNA substrates. We found that Hsh155p interacts directly with Prp5p, the first ATPase that acts during spliceosome assembly, and localized the interacting regions to HEAT (Huntingtin, EF3, PP2A, and TOR1) motifs in SF3B1 associated with disease mutations. Furthermore, we show that mutations in these motifs from both human disease and yeast genetic screens alter the physical interaction with Prp5p, alter branch region specification, and phenocopy mutations in Prp5p. These and other data demonstrate that mutations in Hsh155p and Prp5p alter splicing because they change the direct physical interaction between Hsh155p and Prp5p. This altered physical interaction results in altered loading (i.e., "fidelity") of the BS-U2 duplex into the SF3B complex during prespliceosome formation. These results provide a mechanistic framework to explain the consequences of intron recognition and splicing of SF3B1 mutations found in disease.

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“…In 2012, cohesion complex-encoding gene mutation was reported [40]. Most these mutations were generally identified in all types of myeloid malignancies, while discovery of frequent mutations of splicing machinery, which is highly associated with myelodysplasia and the formation of ring sideroblasts, is important to clarify disease type-and/or phenotypespecific pathological roles of gene mutations [41,42].…”

Section: Introductionmentioning

confidence: 99%

Gene mutations of acute myeloid leukemia in the genome era

Naoe

Kiyoi

2013

Int J Hematol

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Ten years ago, gene mutations found in acute myeloid leukemia (AML) were conceptually grouped into class I mutation, which causes constitutive activation of intracellular signals that contribute to the growth and survival, and class II mutation, which blocks differentiation and/or enhance self-renewal by altered transcription factors. A cooperative model between two classes of mutations has been suggested by murine experiments and partly supported by epidemiological findings. In the last 5 years, comprehensive genomic analysis proceeded to find new gene mutations, which are found in the epigenome-associated enzymes and the molecules never noticed so far. These new mutations apparently increase the complexity and heterogeneity of AML. Although a long list of gene mutations might have been compiled, the entire picture of molecular pathogenesis in AML remains to be elucidated because gene rearrangement, gene copy number, DNA methylation and expression profiles are not fully studied in conjunction with gene mutations. Comprehensive genome research will deepen the understanding of AML to promote the development of new classification and treatment. This review focuses on gene mutations that were recently discovered by genome sequencing.

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SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

Cited by 169 publications

References 32 publications

Comparative Genomics RNAi Screen Identifies Eftud2 as a Novel Regulator of Innate Immunity

Comparative Genomics RNAi Screen Identifies Eftud2 as a Novel Regulator of Innate Immunity

SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing

Gene mutations of acute myeloid leukemia in the genome era

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