Increased Ratios of Internal Organ Volume to Body Mass in Chuvash Polycythemia and HIF-2α Repression of p21^Cip Expression through C-MYC.

Abstract 5039

Chuvash polycythemia, the first hereditary disease associated with dysregulated oxygen sensing, is characterized by homozygous germ-line loss-of-function mutation of VHL (598C>T) resulting in elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, increased red cell mass and propensity to thrombosis. Organ size is determined by the size and number of cells, and its molecular mechanisms are not fully elucidated. Previous work from several groups demonstrated that cell proliferation is regulated in opposite directions by HIF-1α and HIF-2α. HIF-1α inhibits cell proliferation by displacing C-MYC from the promoter of the cyclin-dependent kinase inhibitor, p21^Cip, and inducing its expression, while HIF-2α promotes MYC activity and cell proliferation. We determined the volumes of the liver, spleen, and kidneys and the diameter of the head of the pancreas by computerized tomography in 30 individuals with Chuvash polycythemia and 30 age- and sex-matched Chuvash controls and calculated the ratio of organ volume (or diameter) to body mass. The subjects with Chuvash polycythemia had larger ratios of the liver (P<0.01), spleen (P<0.01), kidneys (P<0.05) and head of the pancreas (P=0.05) than Chuvash controls. To test if HIF contributes to this phenotype, we examined Hif1a^+/− mice and wild type littermates. We found that Hif1a^+/− mice had larger median ratios of liver to body mass (factor of 1.5, P<0.005) and pancreas to body mass (factor of 1.3, P<0.05) than wild type mice. A hepatocyte size analysis revealed that there was no significant difference between Hif1a^+/− and wild type mice. To identify how HIF contributes this phenotype, we performed gene expression profiles in the livers of Hif1a^+/− and wild type littermates. The profiling results and subsequent individual confirmation showed that compared to wild type mice, Hif1a^+/− mice had 2-fold higher HIF-2α mRNA levels (P<0.05) and 9.5-fold lower hepatic p21^Cip mRNA levels (P<0.05). Our results showed that relative to body mass, liver, spleen, kidney and pancreas volumes are increased in Chuvash polycythemia. At least in the liver, this phenotype may result from increased HIF-2α and decreased p21^Cip1 levels, leading to increased hepatocyte proliferation.