Abstract
Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34+ cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34+ cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34+ cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS.
Highlights
The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic malignancies, characterized by blood cytopenias, ineffective hematopoiesis and a hypercellular bone marrow [1]
We have investigated the expression levels of the ABCB7 gene using data from our large microarray dataset on CD34+ cells from MDS patients and healthy controls in order to determine whether the ABCB7 gene is implicated in the common acquired sideroblastic anemia, Refractory Anemia with Ring Sideroblasts (RARS)
We have examined the role of ABCB7, the gene involved in the hereditary X-linked sideroblastic anemia with ataxia (XLSA/A), in the acquired RARS syndrome
Summary
The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic malignancies, characterized by blood cytopenias, ineffective hematopoiesis and a hypercellular bone marrow [1]. Refractory Anemia with Ring Sideroblasts (RARS) is a subtype of MDS in which excess iron accumulates in the form of aberrant mitochondrial ferritin in the mitochondria of the erythroid precursors [2,3]. The hereditary sideroblastic anemias are a heterogeneous group of disorders characterized by the presence of ring sideroblasts in the bone marrow, microcytic hypochromic anemia and typically show X-linked inheritance [5,6,7]. Many of the reported cases of inherited X-linked sideroblastic anemia have been found to be caused by mutations in the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) [8]. A rare inherited X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by mutations of the mitochondrial ATP-binding cassette transporter ABCB7 [9,10]. The phenotype of the ABCB7-deficient cells was characterized by a reduction in proliferation rate that was not rescued by iron supplementation, by signs of iron deficiency, and by a large increase of iron accumulation in the mitochondria that was poorly available to mitochondrial ferritin
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