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Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF3B1 mutated refractory anaemia with ring sideroblasts.
- Source :
-
British journal of haematology [Br J Haematol] 2015 Nov; Vol. 171 (4), pp. 478-90. Date of Electronic Publication: 2015 Aug 10. - Publication Year :
- 2015
-
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.<br /> (© 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)
- Subjects :
- Aged
Aged, 80 and over
Anemia, Refractory blood
Anemia, Sideroblastic blood
Biological Transport genetics
Gene Expression Profiling
Genes, Tumor Suppressor
Genetic Heterogeneity
Humans
Iron metabolism
Phosphoproteins physiology
Protein Isoforms genetics
RNA Splicing Factors
RNA, Messenger genetics
Ribonucleoprotein, U2 Small Nuclear physiology
Sequence Analysis, RNA
Signal Transduction genetics
Anemia, Refractory genetics
Anemia, Sideroblastic genetics
Erythropoiesis genetics
Hemoglobins biosynthesis
Phosphoproteins genetics
RNA Splicing genetics
Ribonucleoprotein, U2 Small Nuclear genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2141
- Volume :
- 171
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- British journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 26255870
- Full Text :
- https://doi.org/10.1111/bjh.13610