The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts

Abstract

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.

Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms

“…Before examining this issue, we want to 23,24 whereas a recent study has shown altered ABCB7 exon usage in primary RARS cells. 36 The interconnection between DNA transcription and RNA splicing, illustrated in Figure 2, is consistent with the conclusion that a somatic SF3B1 mutation may result in reduced transcription and abnormal splicing of ABCB7. SF3B1 mutations showed a non significant trend toward longer survival.…”

“…A recent study by Nikpour et al has tested the hypothesis that a reduced expression of ABCB7 plays a role in the pathophysiology of RARS. 36 The investigators showed that down-regulation of ABCB7 led to markedly reduced erythroid growth in vitro with accumulation of mitochondrial ferritin in immature RBCs. In addition, normalization of ABCB7 expression in RARS erythroblasts rescued aspects of the RARS phenotype.…”

Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron

“…12,26,[28][29][30] Other studies suggested the relationship between SF3B1 mutations and mitochondrial proteins but did not delve into the specific mechanisms or pathways that contribute to iron accumulation or disease phenotype in SF3B1-mutant MDS. 10,31 Using TEM, we found that within RARS/-T, sideroblasts of SF3B1-mutant patients have distinct ultrastructural iron distribution characterized by abundant iron deposits compared with those of WT patients. 12 In the present manuscript, we confirmed that TEM is able to detect a difference in the iron content between mutant and WT RARS/-T patients not appreciated by conventional Prussian blue staining.…”

Iron –sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

“…A distinguishing feature of the disease is the presence of iron- loaded mitochondria (sideroblasts), and defects in heme metabolism with protoporphyrin IX accumulation [273–275]. Defects in ABCB7 have also been proposed to mediate ineffective erythropoiesis in refractory anemia with ring sideroblasts (RARS) [276, 277], a myelodysplastic syndrome (MDS) characterized by mitochondrial ferritin (FTMT) accumulation, and in the refractory anemia with ring sideroblasts and isodicentric (X)(q13) chromosome [278]. It seems that the anemia and the ataxia observed in XLSA/A are related to altered iron homeostasis which leads to mitochondrial iron accumulation in developing red blood cells and in neural cells [279, 280].…”