title: Impact of Splicing Factor Mutations on Pre-mRNA Splicing in the Myelodysplastic Syndromes.
abstract: Splicing is an essential cellular process which is carried out by the spliceosome in order to remove the introns and join the exons present in pre-mRNA transcripts. A variety of spliceosomal mutations have been recently identified in the myelodysplastic syndromes (MDS), a heterogeneous group of hematopoietic stem cell malignancies, revealing a new leukemogenic pathway involving spliceosomal dysfunction. Splicing factor genes are the most frequently mutated genes found in MDS, with mutations occurring in more than half of all patients. The high mutation frequency in different components of the spliceosome in MDS indicates that aberrant splicing may be a common consequence of these mutations in this disorder. RNA sequencing studies using MDS patient bone marrow cells and different mouse models have identified several downstream targets of the splicing factor mutations. Aberrant splicing of these target genes may contribute to MDS pathogenesis, however functional studies are required in order to fully determine the effects of the aberrant isoforms on disease phenotype. Splicing inhibitors are currently being developed and may be used as therapeutic agents to target aberrant pre-mRNA splicing in MDS and other cancers with splicing factor mutations. The mouse models expressing splicing factor mutations may prove particularly valuable for pre-clinical testing of these drugs.
authors.forename: Bon Ham
authors.initials: BH
authors.lastname: Yip
authors.forename: Hamid
authors.initials: H
authors.lastname: Dolatshad
authors.forename: Swagata
authors.initials: S
authors.lastname: Roy
authors.affiliation: andrea.pellagatti@ndcls.ox.ac.uk.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. jacqueline.boultwood@ndcls.ox.ac.uk.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
mesh_terms: D000818:Animals; D006801:Humans; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics*; D017381:Spliceosomes / Q000235:genetics*