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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

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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 2

HIF activity is increased in VhlR/R ES cells.

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HIF activity is increased in VhlR/R ES cells.
               
(A) Wester...
(A) Western blot analysis for HIF-1α and HIF-2α in WT or 2 VhlR/R clones (R/R1 and R/R2) grown under either normoxia (N) or 1.5% hypoxia (H). HIF-1α protein was not detectably stabilized under normoxia; however, normoxic HIF-2α protein levels were greater in VhlR/R cells than in WT cells. (B) Stable clones of 786-O human renal carcinoma cells expressing murine WT Vhl or VhlR200W (R200W) were generated and screened by Western blot for equivalent expression of WT and R200W pVHL. These samples were run on the same gel but were noncontiguous, as indicated by black lines. Normoxic levels of HIF-2α were increased in R200W, but not WT, clones. (C) Secretion of VEGF by ES cells as measured by ELISA. Hypoxic induction of VEGF protein was maintained in VhlR/R cells, similar to control heterozygous (+/–) cells. However, normoxic VEGF protein levels were increased 2- to 3-fold in 3 independent VhlR/R clones compared with control heterozygous cells. **P < 0.0006. (D) WT or VhlR/R ES cells were grown in methylcellulose and allowed to differentiate into EBs for 9 days. The expression of Vegf and Pgk was analyzed by TaqMan real-time PCR. Vegf mRNA levels were increased 1.5- to 2-fold in VhlR/R EBs over WT, while Pgk was upregulated 1.3-fold. *P < 0.03.

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