Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts

A Mupo, M Seiler, V Sathiaseelan, A Pance, Y Yang, A A Agrawal, F Iorio, R Bautista, S Pacharne, K Tzelepis, N Manes, P Wright, E Papaemmanuil, D G Kent, P C Campbell, S Buonamici, N Bolli, G S Vassiliou

Research output: Contribution to journalArticlepeer-review


Heterozygous somatic mutations affecting the spliceosome gene SF3B1 drive age-related clonal hematopoiesis, myelodysplastic syndromes (MDS) and other neoplasms. To study their role in such disorders, we generated knock-in mice with hematopoietic-specific expression of Sf3b1-K700E, the commonest type of SF3B1 mutation in MDS. Sf3b1K700E/+ animals had impaired erythropoiesis and progressive anemia without ringed sideroblasts, as well as reduced hematopoietic stem cell numbers and host-repopulating fitness. To understand the molecular basis of these observations, we analyzed global RNA splicing in Sf3b1K700E/+ hematopoietic cells. Aberrant splicing was associated with the usage of cryptic 3' splice and branchpoint sites, as described for human SF3B1 mutants. However, we found a little overlap between aberrantly spliced mRNAs in mouse versus human, suggesting that anemia may be a consequence of globally disrupted splicing. Furthermore, the murine orthologues of genes associated with ring sideroblasts in human MDS, including Abcb7 and Tmem14c, were not aberrantly spliced in Sf3b1K700E/+ mice. Our findings demonstrate that, despite significant differences in affected transcripts, there is overlap in the phenotypes associated with SF3B1-K700E between human and mouse. Future studies should focus on understanding the basis of these similarities and differences as a means of deciphering the consequences of spliceosome gene mutations in MDS.

Original languageEnglish
Pages (from-to)720-727
Number of pages8
Issue number3
Publication statusPublished - Mar 2017


  • Anemia, Sideroblastic/etiology
  • Animals
  • Disease Models, Animal
  • Gene Targeting
  • Hematopoiesis/genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation
  • Myelodysplastic Syndromes/complications
  • Phenotype
  • Phosphoproteins/genetics
  • RNA Splicing
  • RNA Splicing Factors/genetics


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