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 G-->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(+) 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. 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.

EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors / Perrotta, S; Cucciolla, V; Ferraro, M; Ronzoni, L; Tramontano, A; Rossi, F; Scudieri, Ac; Borriello, A; Roberti, D; Nobili, B; Cappellini, Md; Oliva, A; Amendola, G; FRANCO MIGLIACCIO, ANNA RITA; Mancuso, P; Martin-Padura, I; Bertolini, F; Yoon, D; Prchal, Jt; Della Ragione, F.. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 5:(2010), pp. e12015.1-e12015.17. [10.1371/journal.pone.0012015]

EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors.

FRANCO MIGLIACCIO, ANNA RITA;
2010

Abstract

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 G-->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(+) 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. 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.
2010
EPO receptor gain-of-function causes hereditary polycythemia, alters CD34 cell differentiation and increases circulating endothelial precursors / Perrotta, S; Cucciolla, V; Ferraro, M; Ronzoni, L; Tramontano, A; Rossi, F; Scudieri, Ac; Borriello, A; Roberti, D; Nobili, B; Cappellini, Md; Oliva, A; Amendola, G; FRANCO MIGLIACCIO, ANNA RITA; Mancuso, P; Martin-Padura, I; Bertolini, F; Yoon, D; Prchal, Jt; Della Ragione, F.. - In: PLOS ONE. - ISSN 1932-6203. - ELETTRONICO. - 5:(2010), pp. e12015.1-e12015.17. [10.1371/journal.pone.0012015]
Perrotta, S; Cucciolla, V; Ferraro, M; Ronzoni, L; Tramontano, A; Rossi, F; Scudieri, Ac; Borriello, A; Roberti, D; Nobili, B; Cappellini, Md; Oliva, A; Amendola, G; FRANCO MIGLIACCIO, ANNA RITA; Mancuso, P; Martin-Padura, I; Bertolini, F; Yoon, D; Prchal, Jt; Della Ragione, F.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/466983
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