The von Hippel-Lindau Hereditary Cancer Syndrome: From Bedside to Bench to Bedside

William G. Kaelin, Jr.


Abstract

The von Hippel-Lindau Disease, caused by germline inactivating VHL gene mutations, predisposes people to hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas that are caused by loss of the remaining wild-type VHL allele. Biallelic VHL inactivation is also common in sporadic ccRCCs. The VHL protein, pVHL, forms a ubiquitin ligase that targets the alpha subunits of the HIF transcription factor for degradation. Binding of pVHL to HIFα requires that HIFα be prolyl hydroxylated by the oxygen-sensitive EglN prolyl hydroxylases. HIF activates genes such as VEGF and EPO that promote adaptation to hypoxia. VEGF inhibitors are mainstays for treating ccRCC and HIF2α inhibitors appear promising in phase 2 trials. Conversely, EglN inhibitors, which stabilize HIFα, are being tested for the treatment of anemia and ischemia.


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