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


Authors: Mupo, A.; Seiler, M.; Sathiaseelan, V.; Pance, A.; Yang, Y.; Agrawal, A. A.; Iorio, F.; Bautista, R.; Pacharne, S.; Tzelepis, K.; Manes, N.; Wright, P.; Papaemmanuil, E.; Kent, D. G.; Campbell, P. C.; Buonamici, S.; Bolli, N.; Vassiliou, G. S.
Article Title: Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts
Abstract: 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 hematopoieticspecific 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 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 Sf3b1(K700E/+) mice. Our findings demonstrate that, despite significant differences in affected transcripts, there is overlap in the phenotypes associated with SF3B1-K700Ebetween 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.
Keywords: neoplasms; myelodysplastic syndromes; gene-expression data; cells; vivo; stem; clonal hematopoiesis; sf3b1 mutations; abcb7
Journal Title: Leukemia
Volume: 31
Issue: 3
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2017-03-01
Start Page: 720
End Page: 727
Language: English
ACCESSION: WOS:000395887600024
DOI: 10.1038/leu.2016.251
PROVIDER: wos
PMCID: PMC5336192
PUBMED: 27604819
Notes: Article -- Source: Wos
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