EPO receptor gain-of-function causes hereditary polycythemia, alters cd34+ cell differentiation and increases circulating endothelial precursors

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

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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. Methodology/Principal Findings: We describe a family with polycythemia due to a heterozygous mutation of the EPOR gene that causes a → 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+ 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 EPORnegative 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. Conclusions/Significance: 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.

Original languageEnglish
Article numbere12015
JournalPLoS One
Volume5
Issue number8
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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