Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts
| Autor: | Monika Horvathova, Katarina Kapralova, Zuzana Zidova, Dalibor Dolezal, Dagmar Pospisilova, Vladimir Divoky |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 97, Iss 10 (2012) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2011.059550 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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