Identification of Hepatic-like EPO as a Cause of Polycythemia.
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Martin Laurent, Maric Darko, Idriss Salam, Delamare Marine, Le Roy Amandine, Maaziz Nada, Caillaud Amandine, Si-Tayeb Karim, Robriquet Florence, Lenglet Marion, Erceau Lucie, Bellanné-Chantelot Christine, Plo Isabelle, Aral Bernard, Garrec Céline, Airaud Fabrice, Gianfermi Clara, Antunes Vincent, Keppner Anna, Vincent Sarah Mathilda, Desfontaine Alexis, Modé Nina, Laporte Fabien, Gaignerie Anne, Chariau Caroline, Leray Isabelle, Rogue Coline, David Laurent, Redon Richard, Bézieau Stéphane, Mansour-Hendili Lamisse, Galactéros Frédéric, Maillet Thibault, Pasquet Marlène, Cougoul Pierre, Nloga Anne-Marie, Gardin Claude, Guitton Corinne, Dubruille Viviane, Giacobbi-Milet Vannina, Leblanc Thierry, Kaya Zuhre, Semama Denis, James Chloé, Carillo Serge, Ochmann Marlène, Waage Anders, Mortier Erwan, Maillasson Mike, Quéméner Agnès, Cario Holger, Skoda Radek C, Zermati Yaël, Hoogewijs David, Marchand Alexandre, Girodon François, Gardie Betty
Аннотация
METHODS: We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range and characterized as a novel molecular and functional entity. We investigated the effect of the identified pathogenic variants using EPO promoter-driven luciferase reporter genes. Induced pluripotent stem cells (iPSCs) were generated from patient cells and differentiated into hepatocyte-like EPO-producing cells. Samples of circulating EPO from patients with hereditary erythrocytosis and from healthy newborns were analyzed by means of isoelectric focusing, and EPO activity was assessed.
RESULTS: Three novel variants were identified in the noncoding regions of EPO. Experiments with reporter assays and iPSC-derived hepatocyte-like cells showed that the variants targeted previously uncharacterized regulatory elements of the gene, which, when the variants were present, showed high responsiveness to hypoxia. EPO samples from all the patients showed a modified isoelectric-focusing profile, identical to hepatic EPO that is expressed in premature neonates and in patients with acquired erythrocytosis associated with liver diseases. EPO that was purified from patient plasma and umbilical-cord blood samples showed enhanced EPO receptor signaling activity in vitro, which suggests a potential gain of function linked to the liver-type glycosylation of EPO.
CONCLUSIONS: We found that secondary erythrocytosis can be related to variants in EPO that lead to the production of hepatic-like EPO with an atypical glycosylation pattern and increased activity. (Funded by Région des Pays de la Loire and others; ClinicalTrials.gov number, NCT03957863.).