Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts.
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Mupo, A., Seiler, M., Sathiaseelan, V., Pance, A., Yang, Y., Agrawal, A., Iorio, F., et al. (2017). Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts.. Leukemia, 31 (3), 720-727. https://doi.org/10.1038/leu.2016.251
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. Sf3b1(K700E/+) 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 Sf3b1(K700E/+) hematopoietic cells. Aberrant splicing was associated with usage of cryptic 3' splice and branchpoint sites, as described for human SF3B1 mutants. However, we found 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 Sf3b1(K700E/+) 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.Leukemia accepted article preview online, 08 September 2016. doi:10.1038/leu.2016.251.
Animals, Mice, Transgenic, Humans, Mice, Anemia, Sideroblastic, Myelodysplastic Syndromes, Disease Models, Animal, Phosphoproteins, Gene Targeting, Hematopoiesis, RNA Splicing, Phenotype, Mutation, RNA Splicing Factors
Wellcome Trust (095663/Z/11/A)
External DOI: https://doi.org/10.1038/leu.2016.251
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288816
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/