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Summary  Refractory anaemia with ring sideroblasts ( RARS ) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene   SF 3B1  are found in a majority of  RARS  cases. To explore the link between   SF 3B1  mutations and anaemia, we studied mutated  RARS CD 34 +  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   SF 3B1  mutated cells is most affected, we assessed allele burden during erythroid differentiation  in vitro  and  in vivo  and found that   SF 3B1  mutated erythroblasts showed stable expansion until late erythroblast stage but that terminal maturation to reticulocytes was significantly reduced. In conclusion,   SF 3B1  mutated  RARS  progenitors display impaired splicing with potential downstream consequences for genes of key importance for haemoglobin synthesis and terminal erythroid differentiation.

british journal of haematology

Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in   SF 3B1  mutated refractory anaemia with ring sideroblasts