Details

Autor(en) / Beteiligte

• Perrotta, Silverio
• Cucciolla, Valeria
• Ferraro, Marcella
• Ronzoni, Luisa
• Tramontano, Annunziata
• Rossi, Francesca
• Scudieri, Anna Chiara
• Borriello, Adriana
• Roberti, Domenico
• Nobili, Bruno
• Cappellini, Maria Domenica
• Oliva, Adriana
• Amendola, Giovanni
• Migliaccio, Anna Rita
• Mancuso, Patrizia
• Martin-Padura, Ines
• Bertolini, Francesco
• Yoon, Donghoon
• Prchal, Josef T
• Della Ragione, Fulvio

Titel

EPO Receptor Gain-of-Function Causes Hereditary Polycythemia, Alters CD34.sup.+ Cell Differentiation and Increases Circulating Endothelial Precursors

Ist Teil von

• PloS one, 2010-08, Vol.5 (8), p.e12015

Ort / Verlag

Public Library of Science

Erscheinungsjahr

2010

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Gain-of-function of erythropoietin receptor (EPOR) mutations represent the major cause of primary hereditary polycythemia. EPOR is also found in non-erythroid tissues, although its physiological role is still undefined. We describe a family with polycythemia due to a heterozygous mutation of the EPOR gene that causes a G[right arrow]T change at nucleotide 1251 of exon 8. The novel EPOR G1251T mutation results in the replacement of a glutamate residue by a stop codon at amino acid 393. Differently from polycythemia vera, EPOR G1251T CD34.sup.+ cells proliferate and differentiate towards the erythroid phenotype in the presence of minimal amounts of EPO. Moreover, the affected individuals show a 20-fold increase of circulating endothelial precursors. The analysis of erythroid precursor membranes demonstrates a heretofore undescribed accumulation of the truncated EPOR, probably due to the absence of residues involved in the EPO-dependent receptor internalization and degradation. Mutated receptor expression in EPOR-negative cells results in EPOR and Stat5 phosphorylation. Moreover, patient erythroid precursors present an increased activation of EPOR and its effectors, including Stat5 and Erk1/2 pathway. Our data provide an unanticipated mechanism for autosomal dominant inherited polycythemia due to a heterozygous EPOR mutation and suggest a regulatory role of EPO/EPOR pathway in human circulating endothelial precursors homeostasis.