title: The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts.
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.
authors.affiliation: LRF Molecular Haematology Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, United Kingdom. jacqueline.boultwood@ndcls.ox.ac.uk
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.forename: Maryam
authors.initials: M
authors.lastname: Nikpour
authors.forename: Beena
authors.initials: B
authors.lastname: Pushkaran
authors.forename: Carrie
authors.initials: C
authors.lastname: Fidler
authors.forename: Helen
authors.initials: H
authors.lastname: Cattan
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Littlewood
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Matteo G
authors.initials: MG
authors.lastname: Della Porta
authors.forename: Martin
authors.initials: M
authors.lastname: Jädersten
authors.forename: Sally
authors.initials: S
authors.lastname: Killick
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.forename: David
authors.initials: D
authors.lastname: Bowen
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: James S
authors.initials: JS
authors.lastname: Wainscoat
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000753:Anemia, Refractory / Q000378:metabolism*; D000756:Anemia, Sideroblastic / Q000378:metabolism*; D018952:Antigens, CD34 / Q000096:biosynthesis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA
chemical_list: C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters; D018952:Antigens, CD34