title: von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis.
abstract: The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics.
authors.affiliation: Abramson Family Cancer Research Institute, Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Hickey
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Lam
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Bezman
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000235:genetics; D004921:Erythropoietin / Q000097:blood; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D011086:Polycythemia / Q000097:blood* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013154:Spleen / Q000378:metabolism* / Q000473:pathology; D042442:Vascular Endothelial Growth Factors / Q000097:blood; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human; C494469:VHL protein, mouse