Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

Abstract

BackgroundHypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be improved with high-dose erythropoietin supplementation. The aim of this study was to characterize and compare erythropoiesis in samples from a DMT1-mutant patient before and after treatment with erythropoietin, as well as in a mouse model with a DMT1 mutation, the mk/mk mice. Design and MethodsColony assays were used to compare the in vitro growth of pre-treatment and post-treatment erythroid progenitors in a DMT1-mutant patient. To enable a comparison with human data, high doses of erythropoietin were administered to mk/mk mice. The apoptotic status of erythroblasts, the expression of anti-apoptotic proteins, and the key components of the bone marrow-hepcidin axis were evaluated. ResultsErythropoietin therapy in vivo or the addition of a broad-spectrum caspase inhibitor in vitro significantly improved the growth of human DMT1-mutant erythroid progenitors. A decreased number of apoptotic erythroblasts was detected in the patient's bone marrow after erythropoietin treatment. In mk/mk mice, erythropoietin administration increased activation of signal transducer and activator of transcription 5 (STAT5) and reduced apoptosis in bone marrow and spleen erythroblasts. mk/mk mice propagated on the 129S6/SvEvTac background resembled DMT1-mutant patients in having increased plasma iron but differed by having functional iron deficiency after erythropoietin administration. Co-regulation of hepcidin and growth differentiation factor 15 (GDF15) levels was observed in mk/mk mice but not in the patient. ConclusionsErythropoietin inhibits apoptosis of DMT1-mutant erythroid progenitors and differentiating erythroblasts. Ineffective erythropoiesis associated with defective erythroid iron utilization due to DMT1 mutations has specific biological and clinical features.Key words: DMT1, apoptosis, ineffective erythropoiesis, erythropoietin.Citation: Horvathova M, Kapralova K, Zidova Z, Dolezal D, Pospisilova D, and Divoky V. Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts. Haematologica 2012;97(10):1480-1488. doi:10.3324/haematol.2011 This is an open-access paper.Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

Mechanisms of plasma non‐transferrin bound iron generation: insights from comparing transfused diamond blackfan anaemia with sickle cell and thalassaemia patients

“…The high NTBI in DBA cannot be explained by IE, as markers for this were no higher than in SCD (GDF15) or were virtually absent (sTfR); consistent with erythron maturation arrest in DBA. The high EPO in DBA has been previously reported (Horvathova et al , ), but not with concomitant measurement of hepcidin and sTfR. The high EPO with concomitant high hepcidin (and hepcidin/ferritin ratio) in DBA are consistent with a lack of direct suppression of hepcidin by EPO and the relative absence of IE in the erythron, in contrast to TM.…”

DMT1-Mutant Erythrocytes have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress

“…54.3±0.8 fl in wt mice), reticulocytosis and splenomegaly [14]. We first focused on the in vivo erythrocyte survival.…”

“…DMT1 deficiency leads to severe repression of numerous processes in developing erythroid cells, namely to defective differentiation, reduced survival of erythroid progenitors and increased apoptosis of erythroblasts [14]. On the level of reticulocytes, DMT1 deficiency leads to reduced rate of heme synthesis [32].…”

“…We have previously shown that DMT1 deficiency leads to an impaired erythroid differentiation hallmarked by accumulation of immature forms of erythroblast, accelerated apoptosis of erythroid precursors and diminished survival of erythroid progenitors [14]. In the presented study we aimed to explore whether eryptosis contributes to the pathophysiology of anemia associated with mutations in DMT1.…”

Ribosome profiling uncovers selective mRNA translation associated with eIF2 phosphorylation in erythroid progenitors

“…Iron is a rate limiting factor for the production of hemoglobin during red blood cell development [2], Iron deficiency reduces heme availability, and risks the accumulation and aggregation of free α- and β-globin proteins that damage the cell [3], Therefore, it is important that globin protein synthesis is adjusted to iron availability. The Iron response element binding proteins Irp1 and Irp2 control mRNA stability and translation of transcripts encoding proteins involved in iron homeostasis such as the Transferrin receptor, Ferroportin, and Ferritin [4], Animal models for iron deficiency anemia, or iron depletion upon blood donation, indicate that not only differentiation, but also expansion of immature erythroblasts is impaired [5,6], The cellular mechanism responsible for impaired erythroid recovery upon iron deficiency, however, is poorly understood.…”