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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3562-3565
HEMATOPOIESIS
Paraneoplastic erythrocytosis associated with an inactivating
point mutation of the von Hippel-Lindau gene in a renal cell
carcinoma
Michael S. Wiesener,
Melchior Seyfarth,
Christina Warnecke,
Jan Steffen Jürgensen,
Christian Rosenberger,
Neil V. Morgan,
Eamonn R. Maher,
Ulrich Frei, and
Kai-Uwe Eckardt
From the Department of Nephrology and Medical Intensive
Care, Charité, Humboldt-University, Berlin, Germany; Medical
Clinic and German Heart Center of the Technical University Munich,
Germany; and Department of Paediatrics, Section of Medical and
Molecular Genetics, University of Birmingham, United Kingdom.
The von Hippel-Lindau (VHL) tumor suppressor gene targets
hypoxia-inducible transcription factors (HIFs) for proteasomal
degradation. Erythrocytosis due to inappropriate production of
erythropoietin (EPO), one of the HIF target genes, is a classic albeit
rare finding in patients with renal cancer. We report the clinical to
molecular analysis in a patient in whom a thrombotic myocardial
infarction was the first manifestation of a clear cell renal carcinoma
associated with an elevated serum EPO level (109 U/L) and
erythrocytosis (hemoglobin 200 g/L [20 g/dL]). The tumor
strongly expressed EPO messenger RNA and the 2 regulatory subunits
HIF-1 and HIF-2. Sequence analysis of tumor tissue identified a
point mutation of the VHL gene (nucleotide 701 T>C) with a predicted
amino acid exchange (Leu163Pro). This structural change, although
located at distance to the HIF-binding region, was found to inhibit
binding of HIF-1 to VHL, thus leading to accumulation of HIF, which
drives EPO production.
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