BACKGROUND: Hypochromic 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 METHODS: Colony 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. RESULTS: Erythropoietin 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. CONCLUSIONS: Erythropoietin 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.

• MeSH
• Apoptosis drug effects   genetics   MeSH
• Erythropoietin administration & dosage   pharmacology   MeSH
• Erythroblasts drug effects   metabolism   MeSH
• Erythrocyte Indices MeSH
• Erythroid Precursor Cells drug effects   metabolism   MeSH
• Hepcidins MeSH
• Anemia, Hypochromic drug therapy   genetics   metabolism   MeSH
• Caspases metabolism   MeSH
• Antimicrobial Cationic Peptides metabolism   MeSH
• Bone Marrow drug effects   metabolism   MeSH
• Humans MeSH
• Mutation * MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Cation Transport Proteins genetics   MeSH
• Signal Transduction drug effects   MeSH
• Cell Survival drug effects   genetics   MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Erythropoietin MeSH
• HAMP protein, human MeSH Browser
• Hamp protein, mouse MeSH Browser
• Hepcidins MeSH
• Caspases MeSH
• Antimicrobial Cationic Peptides MeSH
• Cation Transport Proteins MeSH
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2 MeSH Browser
• Iron MeSH