1. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia
- Author
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Romain Carcenac, Michel Leporrier, Stéphane Richard, Michel Barrois, Jean-Jacques Kiladjian, Jacques Pouysségur, André Baruchel, Nathalie M. Mazure, David Hoogewijs, Roland H. Wenger, Anne-Paule Gimenez-Roqueplo, Charline Ladroue, Brigitte Bressac-de Paillerets, Nicole Casadevall, Jean Feunteun, Betty Gardie, Sophie Gad, Fadi Fakhoury, Olivier Hermine, Federica Storti, Bernardo, Elizabeth, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Zürich Center for Integrative Human Physiology (ZIHP), Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Physiology, Service de Génétique [Villejuif], Institut Gustave Roussy (IGR), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hematopoïese et cellules souches normales et pathologiques (U790), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigations Cliniques, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département de Néphrologie [CHU Necker], Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Expert National Cancers Rares INCa 'PREDIR' and Réseau National INCa [AP-HP Hôpital Bicêtre, Paris], Service d'urologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by grants from the 'Association pour la Recherche sur le Cancer' (ARC), the French National Cancer Institute ('INCa', PNES Rein, and Réseau National Prédispositions héréditaires au cancer du rein) and the French Ligue Nationale contre le Cancer (Comités du Cher et de l’Indre) as well as by the HypoxiaNet COST Action TD0901. DH is supported by a postdoctoral Marie Curie IEF Fellowship from the European Commission and the Sassella Stiftung. DH and RHW are supported by grants from the State Secretariat of Education and Research (C10.0106) and from the NCCR Kidney.CH, funded by the SNF., Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Zürich Center for Integrative Human Physiology ( ZIHP ), University of Zürich [Zürich] ( UZH ) -Institute of Physiology, Institut Gustave Roussy ( IGR ), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires ( LRI - EA4062 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d'Hématologie Clinique, CHU Caen-Hôpital Clémenceau, Hematopoïese et cellules souches normales et pathologiques ( U790 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Stabilité Génétique et Oncogenèse ( UMR 8200 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre-Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)
- Subjects
Adult ,Male ,hypoxia inducible factor ,Adolescent ,Tumor suppressor gene ,Mutant ,Procollagen-Proline Dioxygenase ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Polycythemia ,Biology ,medicine.disease_cause ,Germline ,Hypoxia-Inducible Factor-Proline Dioxygenases ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,Hydroxylation ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Germline mutation ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,erythrocytosis ,medicine ,Humans ,PHD2 ,Cells, Cultured ,Germ-Line Mutation ,hypoxia-inducible transcription factor ,030304 developmental biology ,0303 health sciences ,Base Sequence ,Hydrolysis ,Original Articles ,Hematology ,Middle Aged ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,Molecular biology ,3. Good health ,HEK293 Cells ,chemistry ,Hypoxia-inducible factors ,030220 oncology & carcinogenesis ,Female ,Mutant Proteins ,medicine.symptom ,Carcinogenesis - Abstract
International audience; BACKGROUND: Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma.DESIGN AND METHODS: Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively.RESULTS: This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category.CONCLUSIONS: As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.
- Published
- 2011