Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts.
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.
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
A
0000-0002-2771-0462
A
Mupo
H3 Biomedicine, Inc., Cambridge, MA, USA.
M
M
Seiler
Cambridge Stem Cell Institute, Cambridge, UK.
V
V
Sathiaseelan
Malaria Programme, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
A
A
Pance
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
Y
Y
Yang
H3 Biomedicine, Inc., Cambridge, MA, USA.
A A
AA
Agrawal
European Bioinformatics, Institute, Hinxton, Cambridge, UK.
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0000-0001-7063-8913
F
Iorio
LIMS Compute and Infrastructure, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
R
R
Bautista
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
S
S
Pacharne
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
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K
Tzelepis
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
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N
Manes
Department of Pathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
P
P
Wright
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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E
Papaemmanuil
Cambridge Stem Cell Institute, Cambridge, UK.
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DG
Kent
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
P C
PC
Campbell
H3 Biomedicine, Inc., Cambridge, MA, USA.
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S
Buonamici
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Dipartimento di Oncologia ed Onco-Ematologia, Universita' degli Studi di Milano, Milano, Italy.|Dipartimento di Ematologia ed Onco-Ematologia Pediatrica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
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0000-0002-1018-5139
N
Bolli
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.|Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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GS
Vassiliou
D000756:Anemia, Sideroblastic / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D018390:Gene Targeting; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications* / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000378:metabolism
D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C491799:Sf3b1 protein, mouse