Premium
Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF 3B1 mutated refractory anaemia with ring sideroblasts
Author(s) -
Conte Simona,
Katayama Shintaro,
Vesterlund Liselotte,
Karimi Mohsen,
Dimitriou Marios,
Jansson Monika,
MorteraBlanco Teresa,
Unneberg Per,
Papaemmanuil Elli,
Sander Birgitta,
Skoog Tiina,
Campbell Peter,
Walfridsson Julian,
Kere Juha,
HellströmLindberg Eva
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13610
Subject(s) - biology , erythroblast , erythropoiesis , rna splicing , ineffective erythropoiesis , gene , transcriptome , spliceosome , genetics , microbiology and biotechnology , stem cell , haematopoiesis , gene expression , anemia , medicine , rna
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.