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

Abstract

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.

• Authors: Monika Horvathova, Katarina Kapralova, Zuzana Zidova, Dalibor Dolezal, Dagmar Pospisilova, Vladimir Divoky
• Journal: Haematologica (Haematologica) Vol. 97 Issue 10 Pg. 1480-8 (Oct 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22580996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimicrobial Cationic Peptides
• Cation Transport Proteins
• HAMP protein, human
• Hamp protein, mouse
• Hepcidins
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
• Erythropoietin
• Iron
• Caspases

Topics

• Anemia, Hypochromic (drug therapy, genetics, metabolism)
• Animals
• Antimicrobial Cationic Peptides (metabolism)
• Apoptosis (drug effects, genetics)
• Bone Marrow (drug effects, metabolism)
• Caspases (metabolism)
• Cation Transport Proteins (genetics)
• Cell Survival (drug effects, genetics)
• Erythroblasts (drug effects, metabolism)
• Erythrocyte Indices
• Erythroid Precursor Cells (drug effects, metabolism)
• Erythropoietin (administration & dosage, pharmacology)
• Hepcidins
• Humans
• Iron (metabolism)
• Mice
• Mice, Knockout
• Mutation
• Signal Transduction (drug effects)