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.
| Original language | English |
|---|---|
| Pages (from-to) | 1225-1240 |
| Number of pages | 16 |
| Journal | Blood |
| Volume | 132 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Sep 20 2018 |
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ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology
Cite this
Impact of spliceosome mutations on RNA splicing in myelodysplasia : Dysregulated genes/pathways and clinical associations. / Pellagatti, Andrea; Armstrong, Richard N.; Steeples, Violetta; Sharma, Eshita; Repapi, Emmanouela; Singh, Shalini; Sanchi, Andrea; Radujkovic, Aleksandar; Horn, Patrick; Dolatshad, Hamid; Roy, Swagata; Broxholme, John; Lockstone, Helen; Taylor, Stephen; Giagounidis, Aristoteles; Vyas, Paresh; Schuh, Anna; Hamblin, Angela; Papaemmanuil, Elli; Killick, Sally; Malcovati, Luca; Hennrich, Marco L.; Gavin, Anne Claude; Ho, Anthony D.; Luft, Thomas; Hellström-Lindberg, Eva; Cazzola, Mario; Smith, Christopher W.J.; Smith, Stephen; Boultwood, Jacqueline.
In: Blood, Vol. 132, No. 12, 20.09.2018, p. 1225-1240.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Impact of spliceosome mutations on RNA splicing in myelodysplasia
T2 - Dysregulated genes/pathways and clinical associations
AU - Pellagatti, Andrea
AU - Armstrong, Richard N.
AU - Steeples, Violetta
AU - Sharma, Eshita
AU - Repapi, Emmanouela
AU - Singh, Shalini
AU - Sanchi, Andrea
AU - Radujkovic, Aleksandar
AU - Horn, Patrick
AU - Dolatshad, Hamid
AU - Roy, Swagata
AU - Broxholme, John
AU - Lockstone, Helen
AU - Taylor, Stephen
AU - Giagounidis, Aristoteles
AU - Vyas, Paresh
AU - Schuh, Anna
AU - Hamblin, Angela
AU - Papaemmanuil, Elli
AU - Killick, Sally
AU - Malcovati, Luca
AU - Hennrich, Marco L.
AU - Gavin, Anne Claude
AU - Ho, Anthony D.
AU - Luft, Thomas
AU - Hellström-Lindberg, Eva
AU - Cazzola, Mario
AU - Smith, Christopher W.J.
AU - Smith, Stephen
AU - Boultwood, Jacqueline
PY - 2018/9/20
Y1 - 2018/9/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054005808&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054005808&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-04-843771
DO - 10.1182/blood-2018-04-843771
M3 - Article
AN - SCOPUS:85054005808
VL - 132
SP - 1225
EP - 1240
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -