Session: 102. Regulation of Iron Metabolism
Hematology Disease Topics & Pathways:
Anemias, Diseases, thalassemia, red blood cells, Hemoglobinopathies, Biological Processes, Cell Lineage, erythropoiesis, Clinically relevant, iron metabolism
As expected, Erfe transgenic mice, relative to wild-type littermates, displayed a dose-dependent phenotype of liver iron loading with inappropriately low hepcidin expression. At 6 weeks of age liver nonheme iron levels in transgenic mice ranged from ~2 times that of wild-type littermates, in the lowest expressing line, to ~4 times that of wild-type littermates in the highest-expressing line (line H mice). However, elevated Erfe expression did not consistently alter expression of the BMP target genes Id1 or Smad7 in either the liver or bone marrow. Line-H transgenic mice had increased hemoglobin, hematocrit, mean corpuscular volume, and serum iron suggesting that elevated ERFE levels promoted erythropoiesis, at least in part, by suppressing hepcidin and mobilizing more iron, generating a phenotype similar to mouse models of hereditary hemochromatosis.
We also observed phenotypic features that appeared unrelated to iron excess. Line-H breeding diverged from the expected mendelian inheritance ratio of 50% transgenic pups for male mice at weaning age, yielding 37% transgenic pups (N = 108, p =0.0035). Transgenic mice from line-H also had lower body weights and reduced kidney size, accompanied by higher serum urea levels. Additionally, approximately a third of line-H transgenic mice displayed an unusual behavior characterized by repetitive circling and an impaired righting reflex, suggesting vestibular dysfunction. These findings of stunted growth, renal impairment and behavioral abnormalities raise the possibility that elevated ERFE levels may exert iron-independent adverse effects in congenital anemias with ineffective erythropoiesis and in β-thalassemia, perhaps by inhibiting BMP-dependent developmental signals. Future studies using the graded expression of the Erfe-transgene combined with mouse models of dyserythropoiesis will facilitate analysis of the contribution of varying levels of ERFE to the pathophysiology of ineffective erythropoiesis and lay the foundation for pharmacologically targeting ERFE for the amelioration of the hematologic and nonhematologic manifestations of anemias with ineffective erythropoiesis.
Disclosures: Nemeth: Vifor: Consultancy; Protagonist: Consultancy; Ionis Pharmaceuticals: Consultancy; Silarus Therapeutics: Current equity holder in private company; Intrinsic LifeSciences: Current equity holder in private company. Ganz: Disc Medicine: Consultancy; Silarus Therapeutics: Current equity holder in private company; Intrinsic LifeSciences: Current equity holder in private company; Ambys: Consultancy; Sierra Oncology: Consultancy; Rockwell: Consultancy; Gossamer Bio: Consultancy; American Regent: Consultancy; Global Blood Therapeutics: Consultancy; Astellas: Consultancy; Akebia: Consultancy; Vifor: Consultancy; Ionis Pharmaceuticals: Consultancy.