The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts.
Refractory anemia with ring sideroblasts (RARS) is characterized by mitochondrial ferritin (FTMT) accumulation and markedly suppressed expression of the iron transporter ABCB7. To test the hypothesis that ABCB7 is a key mediator of ineffective erythropoiesis of RARS, we modulated its expression in hematopoietic cells. ABCB7 up and downregulation did not influence growth and survival of K562 cells. In normal bone marrow, ABCB7 downregulation reduced erythroid differentiation, growth and colony formation, and resulted in a gene expression pattern similar to that observed in intermediate RARS erythroblasts, and in the accumulation of FTMT. Importantly, forced ABCB7 expression restored erythroid colony growth and decreased FTMT expression level in RARS CD34+ marrow cells. Mutations in the SF3B1 gene, a core component of the RNA splicing machinery, were recently identified in a high proportion of patients with RARS and 11 of the 13 RARS patients in this study carried this mutation. Interestingly, ABCB7 exon usage differed between normal bone marrow and RARS, as well as within the RARS cohort. In addition, SF3B1 silencing resulted in downregulation of ABCB7 in K562 cells undergoing erythroid differentiation. Our findings support that ABCB7 is implicated in the phenotype of acquired RARS and suggest a relation between SF3B1 mutations and ABCB7 downregulation.
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Maryam
M
Nikpour
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.|Department of Medicine, Skaraborgs Hospital, Skovde, Sweden.
Christian
C
Scharenberg
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Anquan
A
Liu
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Simona
S
Conte
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Mohsen
M
Karimi
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Teresa
T
Mortera-Blanco
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Valentina
V
Giai
LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK.
Marta
M
Fernandez-Mercado
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK, Department of Haematology, University of Cambridge, Cambridge, UK.
Elli
E
Papaemmanuil
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Kari
K
Högstrand
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Monika
M
Jansson
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Inger
I
Vedin
LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK.
James Stephen
JS
Wainscoat
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK, Department of Haematology, University of Cambridge, Cambridge, UK.
Peter
P
Campbell
Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Mario
M
Cazzola
LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK.
Jacqueline
J
Boultwood
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Alf
A
Grandien
Karolinska Institutet, Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Eva
E
Hellström-Lindberg
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000235:genetics*; D000756:Anemia, Sideroblastic / Q000235:genetics*; D015331:Cohort Studies; D015536:Down-Regulation; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012326:RNA Splicing; D060888:Real-Time Polymerase Chain Reaction
C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters