title: Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF3B1 mutated refractory anaemia with ring sideroblasts.
abstract: Refractory anaemia with ring sideroblasts (RARS) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene SF3B1 are found in a majority of RARS cases. To explore the link between SF3B1 mutations and anaemia, we studied mutated RARS CD34(+) marrow cells with regard to transcriptome sequencing, splice patterns and mutational allele burden during erythroid differentiation. Transcriptome profiling during early erythroid differentiation revealed a marked up-regulation of genes involved in haemoglobin synthesis and in the oxidative phosphorylation process, and down-regulation of mitochondrial ABC transporters compared to normal bone marrow. Moreover, mis-splicing of genes involved in transcription regulation, particularly haemoglobin synthesis, was confirmed, indicating a compromised haemoglobinization during RARS erythropoiesis. In order to define the phase during which erythroid maturation of SF3B1 mutated cells is most affected, we assessed allele burden during erythroid differentiation in vitro and in vivo and found that SF3B1 mutated erythroblasts showed stable expansion until late erythroblast stage but that terminal maturation to reticulocytes was significantly reduced. In conclusion, SF3B1 mutated RARS progenitors display impaired splicing with potential downstream consequences for genes of key importance for haemoglobin synthesis and terminal erythroid differentiation.
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Simona
authors.initials: S
authors.lastname: Conte
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition and Center for Innovative Medicine, Stockholm, Sweden.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Katayama
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition and Center for Innovative Medicine, Stockholm, Sweden.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Vesterlund
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Marios
authors.initials: M
authors.lastname: Dimitriou
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Jansson
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mortera-Blanco
authors.affiliation: Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Unneberg
authors.affiliation: Cancer Genetics & Genomics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Karolinska Institutet, Department of Laboratory Medicine, Division of Pathology, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition and Center for Innovative Medicine, Stockholm, Sweden.
authors.forename: Tiina
authors.initials: T
authors.lastname: Skoog
authors.affiliation: Cancer Genetics & Genomics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Julian
authors.initials: J
authors.lastname: Walfridsson
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition and Center for Innovative Medicine, Stockholm, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Karolinska Institutet, Department of Medicine (Huddinge), Centre for Hematology and Regenerative Medicine, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000097:blood / Q000235:genetics*; D000756:Anemia, Sideroblastic / Q000097:blood / Q000235:genetics*; D001692:Biological Transport / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics*; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D018740:Genetic Heterogeneity; D006454:Hemoglobins / Q000096:biosynthesis*; D006801:Humans; D007501:Iron / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics* / Q000502:physiology; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: D006454:Hemoglobins; D010750:Phosphoproteins; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D007501:Iron
keywords: SF3B1; erythropoiesis; myelodysplastic syndromes; refractory anaemia with ring sideroblasts