Academic Journal
Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors.
| العنوان: | Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors. |
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| المؤلفون: | Poggi, Marjorie, Canault, Matthias, Favier, Marie, Turro, Ernest, Saultier, Paul, Ghalloussi, Dorsaf, Baccini, Veronique, Vidal, Lea, Mezzapesa, Anna, Chelghoum, Nadjim, Mohand Oumoussa, Badreddine, Falaise, Céline, Favier, Rémi, Ouwehand, Willem H., Fiore, Mathieu, Peiretti, Franck, Morange, Pierre-Emmanuel, Saut, Noémie, Bernot, Denis, Greinacher, Andreas, Nurden, Alan T., Nurden, Paquita, Freson, Kathleen, Trégouët, David-Alexandre, Raslova, Hana, Alessi, Marie-Christine |
| المساهمون: | Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Wellcome Trust Sanger Institute Cambridge, NOVABUILD, parent, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de pédiatrie, d'hématologie et d'oncologie Hôpital de La Timone - APHM, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone CHU - APHM (TIMONE), CNR Institute of Electronics, Computer and Telecommunication Engineering Torino (CNR, CNR Istituto di elettronica e di ingegneria dell'informazione e delle telecomunicazioni (CNR, National Research Council of Italy, IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux), Center for Molecular and Vascular Biology, Catholic University of Leuven = Katholieke Universiteit Leuven (KU Leuven), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition CHU Pitié Salpêtrière (IHU ICAN), CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-IAHU-05, FDM20150633607, (NIHR) RG65966 (FWO-Vlaanderen, Belgium) G.0B17.13N (BOF KU Leuven, Belgium) OT/14/098 |
| المصدر: | ISSN: 0390-6078. |
| بيانات النشر: | HAL CCSD Ferrata Storti Foundation |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | germ-line cells, hematopoietic cell, mégacaryocyte, thrombocyte, progéniteur érythrocytaire, cellule germinale, cellule hematopoietique, séquence d'adn, gène autosomal, hémopathie, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] |
| الوصف: | International audience ; Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to corepressors. We also observed a large expansion of megakaryocyte colony-forming units derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34(+) cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton CDC42 and RHOA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, and spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34(+) cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts, while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production, and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/27663637; PUBMED: 27663637; PUBMEDCENTRAL: PMC5286936 |
| DOI: | 10.3324/haematol.2016.147694 |
| الاتاحة: | https://hal.science/hal-01478347 https://hal.science/hal-01478347v1/document https://hal.science/hal-01478347v1/file/282.full.pdf https://doi.org/10.3324/haematol.2016.147694 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.F2BD4717 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3324/haematol.2016.147694 |
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