von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α signaling and splenic erythropoiesis
Michele M. Hickey, … , W. Kimryn Rathmell, M. Celeste Simon
Michele M. Hickey, … , W. Kimryn Rathmell, M. Celeste Simon
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3879-3889. https://doi.org/10.1172/JCI32614.
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Research Article Hematology

von Hippel–Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2α 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–1α (HIF-1α) 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 (VhlR/R). VhlR/R mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2α isoform, was upregulated in ES cells and tissues from VhlR/R mice. Furthermore, we observed a striking phenotype in VhlR/R spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of VhlR/R splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2α genes promotes splenic erythropoiesis, resulting in the development of polycythemia in VhlR/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

Michele M. Hickey, Jennifer C. Lam, Natalie A. Bezman, W. Kimryn Rathmell, M. Celeste Simon

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Figure 3

VhlR/R mice develop polycythemia.

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VhlR/R mice develop polycythemia. (A) The snout and paw...
(A) The snout and paws of VhlR/R mice appeared redder in color than WT littermates. (B) There was no difference in the hematocrit levels based on genotype at 5–6 weeks; however, the hematocrit of VhlR/R mice became significantly greater than WT and VhlR/+ mice with increasing age (9% higher at 14–16 weeks and 11.8% higher at 26–29 weeks). *P < 0.0005. (C and D) Total red blood cell number (C) and hemoglobin concentration (D) were 14% and 22% greater, respectively, in VhlR/R mice than in WT mice. *P < 0.004; **P < 0.0007. (E) Total white blood cell number was also increased by 36% in VhlR/R mice. #P < 0.059 (trending toward significance). (F) The number of platelets was not significantly increased in VhlR/R mice. Results in C–F represent pooled data from mice aged 9–15 months.