Altered splicing and cytoplasmic levels of tRNA synthetases in SF3B1-mutant myelodysplastic syndromes as a therapeutic vulnerability

Sci Rep. 2019 Feb 25;9(1):2678. doi: 10.1038/s41598-019-39591-7.


Myelodysplastic syndromes (MDS) are haematopoietic malignancies that are characterised by a heterogeneous clinical course. In recent years, sequencing efforts have uncovered recurrent somatic mutations within RNA splicing factors, including SF3B1, SRSF2, U2AF1 and ZRSR2. The most frequently mutated gene is SF3B1, mutated in 17% of MDS patients. While SF3B1 mutations and their effects on splicing have been well characterised, much remains to be explored about their more far-reaching effects on cellular homeostasis. Given that mRNA splicing and nuclear export are coordinated processes, we hypothesised that SF3B1 mutation might also affect export of certain mRNAs and that this may represent a targetable pathway for the treatment of SF3B1-mutant MDS. We used CRISPR/Cas9-genome editing to create isogenic cellular models. Comprehensive transcriptome and proteome profiling of these cells identified alterations in the splicing and export of components of the translational machinery, primarily tRNA synthetases, in response to the SF3B1 K700E mutation. While steady-state protein synthesis was unaffected, SF3B1 mutant cells were more sensitive to the clinically-relevant purine analogue, 8-azaguanine. In this study, we also demonstrated that 8-azaguanine affects splicing. Our results suggest that the simultaneous targeting of RNA metabolism and splicing by 8-azaguanine represents a therapeutic opportunity for SF3B1-mutant myelodysplastic syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acyl-tRNA Synthetases / genetics*
  • Amino Acyl-tRNA Synthetases / metabolism
  • Cell Line, Tumor
  • Cytoplasm / enzymology*
  • Gene Editing / methods
  • Gene Expression Profiling / methods
  • HEK293 Cells
  • Humans
  • K562 Cells
  • Mutation*
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / therapy
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Protein Biosynthesis / genetics
  • Proteome / genetics
  • Proteome / metabolism
  • Proteomics / methods
  • RNA Splicing Factors / genetics*
  • RNA Splicing Factors / metabolism
  • RNA Splicing*


  • Phosphoproteins
  • Proteome
  • RNA Splicing Factors
  • SF3B1 protein, human
  • Amino Acyl-tRNA Synthetases