title: 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.
  
  
  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.affiliation: Department of Biology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Monika
authors.initials: M
authors.lastname: Horvathova
authors.forename: Katarina
authors.initials: K
authors.lastname: Kapralova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zidova
authors.forename: Dalibor
authors.initials: D
authors.lastname: Dolezal
authors.forename: Dagmar
authors.initials: D
authors.lastname: Pospisilova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divoky
mesh_terms: D000747:Anemia, Hypochromic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004900:Erythroblasts / Q000187:drug effects / Q000378:metabolism*; D004909:Erythrocyte Indices; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism*; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects*; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D023181:Antimicrobial Cationic Peptides; D020169:Caspases; D027682:Cation Transport Proteins; D004921:Erythropoietin; D064451:Hepcidins; D007501:Iron; D000099236:Solute Carrier Family 11, Member 2; C578702:HAMP protein, human; C579599:Hamp protein, mouse