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RNA sequencing of bone marrow CD34+ cells from myelodysplastic syndrome patients with and without SF3B1 mutation and from healthy controls

ABSTRACT: The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34+ cells from MDS patients with SF3B1 mutations using RNA-sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared to wildtype cases include genes involved in MDS pathogenesis (ASXL1, CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7, SLC25A37) and RNA splicing/processing (PRPF8, HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. Our data indicate that SF3B1 plays a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63569 | GEO | 2014/11/22

SECONDARY ACCESSION(S): PRJNA268220

REPOSITORIES: GEO

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Project description:Myelodysplastic syndromes (MDS) are a group of clonal hematological disorders characterized by ineffective hematopoiesis with morphological evidence of marrow cell dysplasia resulting in peripheral blood cytopenia. Microarray technology has permitted a refined high-throughput mapping of the transcriptional activity in the human genome. Noncoding-RNAs (ncRNAs) transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression, and in the regulation of exon-skipping and intron retention. Characterization of ncRNAs in progenitor cells and stromal cells of MDS patients could be strategic for understanding gene expression regulation in this disease. In this study, gene expression profiles of CD34+ and stromal cells of MDS patients with refractory anemia with ringed sideroblasts (RARS) subgroup were compared those of healthy individuals, using 44k combined intron-exon oligoarrays, which included probes for protein-coding genes, for sense and antisense strands of totally intronic noncoding (TIN) and for partially intronic noncoding (PIN) RNAs. In CD34+ cells of MDS-RARS patients, 217 genes were significantly differentially expressed (q-value < 0.01) in comparison to healthy individuals, of which 68 (31%) were noncoding transcripts. In stromal cells of MDS-RARS, 13 genes were significantly differentially expressed (q-value < 0.05) in comparison to healthy individuals, of which 4 (30%) were noncoding transcripts. These results demonstrated, for the first time, in CD34+ cells and stromal cells the differential ncRNA expression profile between MDS-RARS and healthy individuals, suggesting that ncRNAs may play an important role during the development of myelodysplastic syndromes. Bone marrow (BM) CD34+ cell samples were collected from 4 healthy subjects and from 4 MDS patients. Stromal samples were collected from 4 healthy subjects and 3 MDS patients. All patients were diagnosed as RARS according to the French-American-British (FAB) classification and did not present chromosomal abnormalities; they received no growth factors or any further MDS treatment.

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RNA sequencing of bone marrow CD34+ cells from myelodysplastic syndrome patients with and without SF3B1 mutation and from healthy controls

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