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


RESULTS
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
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.
Perrotta
Silverio
S
Department of Pediatrics, Second University of Naples, Naples, Italy.
Cucciolla
Valeria
V
Ferraro
Marcella
M
Ronzoni
Luisa
L
Tramontano
Annunziata
A
Rossi
Francesca
F
Scudieri
Anna Chiara
AC
Borriello
Adriana
A
Roberti
Domenico
D
Nobili
Bruno
B
Cappellini
Maria Domenica
MD
Oliva
Adriana
A
Amendola
Giovanni
G
Migliaccio
Anna Rita
AR
Mancuso
Patrizia
P
Martin-Padura
Ines
I
Bertolini
Francesco
F
Yoon
Donghoon
D
Prchal
Josef T
JT
Della Ragione
Fulvio
F
D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism*; D001483:Base Sequence; D016022:Case-Control Studies; D002454:Cell Differentiation; D002462:Cell Membrane / Q000473:pathology; D049109:Cell Proliferation; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D020014:K562 Cells; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011086:Polycythemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary; D017467:Receptors, Erythropoietin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D055815:Young Adult
D018952:Antigens, CD34; D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor