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Leukemia. 2017 Mar;31(3):720-727. doi: 10.1038/leu.2016.251. Epub 2016 Sep 8.

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

Author information

1
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
2
H3 Biomedicine, Inc., Cambridge, MA, USA.
3
Cambridge Stem Cell Institute, Cambridge, UK.
4
Malaria Programme, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
5
European Bioinformatics, Institute, Hinxton, Cambridge, UK.
6
LIMS Compute and Infrastructure, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
7
Department of Pathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
8
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
10
Dipartimento di Oncologia ed Onco-Ematologia, Universita' degli Studi di Milano, Milano, Italy.
11
Dipartimento di Ematologia ed Onco-Ematologia Pediatrica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
12
Department of Haematology, University of Cambridge, Cambridge, UK.
13
Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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 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.

PMID:
27604819
PMCID:
PMC5336192
DOI:
10.1038/leu.2016.251
[Indexed for MEDLINE]
Free PMC Article

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