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

PloS One
Silverio PerrottaFulvio Della Ragione

Abstract

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-->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. Our data provide an unanticipated mechanis...Continue Reading

References

May 27, 1988·Deutsche medizinische Wochenschrift·W QueisserP Worst
Jun 30, 1995·Science·J T PrchalL Sokol
May 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·A de la ChapelleE Juvonen
Feb 7, 2001·Proceedings of the National Academy of Sciences of the United States of America·V DivokyJ T Prchal
Feb 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·Murat CelikMichael Brines
Jun 18, 2002·Blood Cells, Molecules & Diseases·Giovanni MigliaccioThalia Papayannopoulou
Oct 17, 2003·Hematology/oncology Clinics of North America·Josef T Prchal
Jun 26, 2004·Journal of Pediatric Hematology/oncology·Tom Van MaerkenJoris Verlooy
Dec 14, 2004·The Oncologist·Francis Farrell, Adrian Lee
Jan 6, 2005·JAMA : the Journal of the American Medical Association·Kenneth MaieseZhao Zhong Chong
Aug 10, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Brian Leyland-JonesEls Vercammen
Oct 27, 2005·Blood·Steve ElliottC Glenn Begley
Mar 3, 2006·The Journal of Clinical Investigation·Gregory D Longmore
Mar 4, 2006·International Journal of Hematology·Masahiro ImamuraYoshihisa Kodera
Apr 13, 2006·European Journal of Haematology·Lambros K BourantasIoannis Georgiou
Apr 19, 2006·Cancer Research·Adriana BorrielloFulvio Della Ragione
Sep 20, 2006·Molecular and Cellular Biology·Stéphane PelletierJames N Ihle
Oct 10, 2006·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Michael HenkeFrank Pajonk
Oct 13, 2006·Nature Reviews. Cancer·Francesco BertoliniRobert S Kerbel
Feb 3, 2007·The New England Journal of Medicine·Linda M ScottAnthony R Green
Mar 17, 2007·Circulation Research·Paolo Madeddu, Costanza Emanueli
May 2, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Fulvio Della RagioneSilverio Perrotta
Jun 15, 2007·The New England Journal of Medicine·Gregory D Longmore
Sep 25, 2007·Blood Cells, Molecules & Diseases·Luisa RonzoniMaria Domenica Cappellini
Jan 26, 2010·British Journal of Haematology·Lily J HuangGamze B Bulut

Citations

Feb 2, 2016·La Revue de médecine interne·T BarbaM Pavic
Oct 12, 2013·Human Mutation·Celeste BentoECE-Consortium
Sep 27, 2015·Revista brasileira de hematologia e hemoterapia·Renata Mendes de Freitas, Carlos Magno da Costa Maranduba
Jun 3, 2011·The Biochemical Journal·Que T LambertGary W Reuther
Jun 6, 2012·Proceedings of the National Academy of Sciences of the United States of America·Jun LiuPramod K Mistry
Feb 6, 2016·The Journal of Biological Chemistry·Pardeep HeirMichael Ohh
Oct 2, 2018·Communications Biology·Gudjon R OskarssonKari Stefansson

Related Concepts

Cell Differentiation Process
Plasma Membrane
Protoplasm
Phosphorylation
Erythrocytosis
Erythroid Progenitor Cells
Nested Case-Control Studies
Tertiary Protein Structure
Erythropoietin Receptor
CD34 Antigens

Related Feeds

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.

Bioinformatics in Biomedicine

Bioinformatics in biomedicine incorporates computer science, biology, chemistry, medicine, mathematics and statistics. Discover the latest research on bioinformatics in biomedicine here.

© 2021 Meta ULC. All rights reserved