Impact of spliceosome mutations on RNA splicing in myelodysplasia: Dysregulated genes/pathways and clinical associations Journal Article


Authors: Pellagatti, A.; Armstrong, R. N.; Steeples, V.; Sharma, E.; Repapi, E.; Singh, S.; Sanchi, A.; Radujkovic, A.; Horn, P.; Dolatshad, H.; Roy, S.; Broxholme, J.; Lockstone, H.; Taylor, S.; Giagounidis, A.; Vyas, P.; Schuh, A.; Hamblin, A.; Papaemmanuil, E.; Killick, S.; Malcovati, L.; Hennrich, M. L.; Gavin, A. C.; Ho, A. D.; Luft, T.; HellstroĢˆm-Lindberg, E.; Cazzola, M.; Smith, C. W. J.; Smith, S.; Boultwood, J.
Article Title: Impact of spliceosome mutations on RNA splicing in myelodysplasia: Dysregulated genes/pathways and clinical associations
Abstract: SF3B1, SRSF2, and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow 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 CD34+ cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology. Copyright 2011 by The American Society of Hematology; all rights reserved.
Keywords: survival; controlled study; human tissue; gene mutation; major clinical study; pathophysiology; gene; cd34 antigen; erythroid precursor cell; genetic association; myelodysplastic syndrome; messenger rna; hematopoietic stem cell; spliceosome; myeloid progenitor cell; cd14 antigen; rna splicing; sirtuin; platelet count; rna sequence; interleukin 1beta converting enzyme; disorders of mitochondrial functions; focal adhesion; heme; gene expression level; next generation sequencing; human; priority journal; article; receptor type tyrosine protein phosphatase c; cxx1 gene; dynll1 gene; ercc3 gene; gpr108 gene; lat2 gene; nicn1 gene; parvg gene; ppox gene; sept2 gene; snrpn gene
Journal Title: Blood
Volume: 132
Issue: 12
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2018-09-20
Start Page: 1225
End Page: 1240
Language: English
DOI: 10.1182/blood-2018-04-843771
PUBMED: 29930011
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 November 2018 -- Source: Scopus
Altmetric Score
MSK Authors