Page 31 - Haematologica-April 2018

Red Cell Biology & Its Disorders
New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis
Ferrata Storti Foundation
Florence Pasquier,1,2,3,4 Caroline Marty,1,2,4 Thomas Balligand,5
Frédérique Verdier,4,6 Sarah Grosjean,1,2,4 Vitalina Gryshkova,5 Hana Raslova,1,2,4 Stefan N. Constantinescu,5 Nicole Casadevall,1,7 William Vainchenker,1,2,4 Christine Bellanné-Chantelot1,8* and Isabelle Plo1,2,4*
1INSERM, UMR 1170, Gustave Roussy, Laboratoire d’Excellence GR-Ex, Villejuif, France; 2Université Paris-Sud, UMR 1170, Gustave Roussy, Villejuif, France; 3Service d’Hématologie, Département d’Oncologie Médicale, Gustave Roussy, Villejuif, France; 4Laboratoire d’Excellence GR-Ex, Paris, France; 5Ludwig Institute for Cancer Research, and Université Catholique de Louvain, de Duve Institute, Brussels, Belgium; 6INSERM U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, France; 7Laboratoire d'Hématologie, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris, France and 8Département de Génétique, Hôpital Universitaire Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, France
Haematologica 2018 Volume 103(4):575-586
* CB-C and IP contributed equally to this work.
ABSTRACT
Primary familial and congenital polycythemia is characterized by ery- thropoietin hypersensitivity of erythroid progenitors due to germline nonsense or frameshift mutations in the erythropoietin receptor gene. All mutations so far described lead to the truncation of the C-terminal receptor sequence that contains negative regulatory domains. Their removal is presented as sufficient to cause the erythropoietin hypersensitivity phenotype. Here we provide evidence for a new mech- anism whereby the presence of novel sequences generated by frameshift mutations is required for the phenotype rather than just extensive trun- cation resulting from nonsense mutations. We show that the erythropoi- etin hypersensitivity induced by a new erythropoietin receptor mutant, p.Gln434Profs*11, could not be explained by the loss of negative signal- ing and of the internalization domains, but rather by the appearance of a new C-terminal tail. The latter, by increasing erythropoietin receptor dimerization, stability and cell-surface localization, causes pre-activation of erythropoietin receptor and JAK2, constitutive signaling and hypersen- sitivity to erythropoietin. Similar results were obtained with another mutant, p.Pro438Metfs*6, which shares the same last five amino acid residues (MDTVP) with erythropoietin receptor p.Gln434Profs*11, con- firming the involvement of the new peptide sequence in the erythropoi- etin hypersensitivity phenotype. These results suggest a new mechanism that might be common to erythropoietin receptor frameshift mutations. In summary, we show that primary familial and congenital polycythemia is more complex than expected since distinct mechanisms are involved in the erythropoietin hypersensitivity phenotype, according to the type of erythropoietin receptor mutation.
Introduction
Primary erythrocytosis (also known as primary familial and congenital poly- cythemia, PFCP) is a pathology of erythroid progenitors, which display hypersen- sitivity to erythropoietin.1-14 This rare inherited entity is usually passed down with an autosomal dominant pattern with complete penetrance.2-6,8-14 PFCP is character- ized by an isolated primary polycythemia in which an increased red cell mass is associated with subnormal serum erythropoietin levels. It can therefore mimic the clinical presentation of polycythemia vera. However, the hematopoiesis is poly-
Correspondence:
isabelle.plo@gustaveroussy.fr or christine.bellanne-chantelot@aphp.fr
Received: July 12, 2017.
Accepted: December 21, 2017. Pre-published: December 21, 2017.
doi:10.3324/haematol.2017.176370
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/575
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