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.