A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.
Identifieur interne : 002471 ( Main/Exploration ); précédent : 002470; suivant : 002472A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.
Auteurs : Ernest Turro [Royaume-Uni] ; Daniel Greene [Royaume-Uni] ; Anouck Wijgaerts [Belgique] ; Chantal Thys [Belgique] ; Claire Lentaigne [Royaume-Uni] ; Tadbir K. Bariana [Royaume-Uni] ; Sarah K. Westbury [Royaume-Uni] ; Anne M. Kelly [Royaume-Uni] ; Dominik Selleslag [Belgique] ; Jonathan C. Stephens [Royaume-Uni] ; Sofia Papadia [Royaume-Uni] ; Ilenia Simeoni [Royaume-Uni] ; Christopher J. Penkett [Royaume-Uni] ; Sofie Ashford [Royaume-Uni] ; Antony Attwood [Royaume-Uni] ; Steve Austin [Royaume-Uni] ; Tamam Bakchoul [Allemagne] ; Peter Collins [Royaume-Uni] ; Sri V V. Deevi [Royaume-Uni] ; Rémi Favier [France] ; Myrto Kostadima [Royaume-Uni] ; Michele P. Lambert [États-Unis] ; Mary Mathias [Royaume-Uni] ; Carolyn M. Millar [Royaume-Uni] ; Kathelijne Peerlinck [Belgique] ; David J. Perry [Royaume-Uni] ; Sol Schulman [États-Unis] ; Deborah Whitehorn [Royaume-Uni] ; Christine Wittevrongel [Belgique] ; Marc De Maeyer [Belgique] ; Augusto Rendon [Royaume-Uni] ; Keith Gomez [Royaume-Uni] ; Wendy N. Erber [Australie] ; Andrew D. Mumford [Royaume-Uni] ; Paquita Nurden [France] ; Kathleen Stirrups [Royaume-Uni] ; John R. Bradley [Royaume-Uni] ; F Lucy Raymond [Royaume-Uni] ; Michael A. Laffan [Royaume-Uni] ; Chris Van Geet [Belgique] ; Sylvia Richardson [Royaume-Uni] ; Kathleen Freson [Belgique] ; Willem H. Ouwehand [Royaume-Uni]Source :
- Science translational medicine [ 1946-6242 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Cellules COS, Cercopithecus aethiops, Danio zébré, Femelle, Humains, Hématopoïèse, Hémorragie (), Hémorragie (génétique), Mutation (génétique), Myélofibrose primitive (), Myélofibrose primitive (génétique), Mâle, Os et tissu osseux (anatomopathologie), Pedigree, Phénotype, Plaquettes (anatomopathologie), Thrombopénie (), Thrombopénie (génétique), Transfection, src-Family kinases (génétique).
- MESH :
- anatomopathologie : Os et tissu osseux, Plaquettes.
- génétique : Hémorragie, Mutation, Myélofibrose primitive, Thrombopénie, src-Family kinases.
- Animaux, Cellules COS, Cercopithecus aethiops, Danio zébré, Femelle, Humains, Hématopoïèse, Hémorragie, Myélofibrose primitive, Mâle, Pedigree, Phénotype, Thrombopénie, Transfection.
English descriptors
- KwdEn :
- Animals, Blood Platelets (pathology), Bone and Bones (pathology), COS Cells, Cercopithecus aethiops, Female, Hematopoiesis, Hemorrhage (complications), Hemorrhage (genetics), Humans, Male, Mutation (genetics), Pedigree, Phenotype, Primary Myelofibrosis (complications), Primary Myelofibrosis (genetics), Thrombocytopenia (complications), Thrombocytopenia (genetics), Transfection, Zebrafish, src-Family Kinases (genetics).
- MESH :
- chemical , genetics : src-Family Kinases.
- complications : Hemorrhage, Primary Myelofibrosis, Thrombocytopenia.
- genetics : Hemorrhage, Mutation, Primary Myelofibrosis, Thrombocytopenia.
- pathology : Blood Platelets, Bone and Bones.
- Animals, COS Cells, Cercopithecus aethiops, Female, Hematopoiesis, Humans, Male, Pedigree, Phenotype, Transfection, Zebrafish.
Abstract
The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors.
DOI: 10.1126/scitranslmed.aad7666
PubMed: 26936507
Affiliations:
- Allemagne, Australie, Belgique, France, Royaume-Uni, États-Unis
- Angleterre, Angleterre de l'Est, Massachusetts, Pennsylvanie, Province du Brabant flamand
- Cambridge, Heverlee, Louvain
- Université de Cambridge
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National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Greene, Daniel" sort="Greene, Daniel" uniqKey="Greene D" first="Daniel" last="Greene">Daniel Greene</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wijgaerts, Anouck" sort="Wijgaerts, Anouck" uniqKey="Wijgaerts A" first="Anouck" last="Wijgaerts">Anouck Wijgaerts</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Thys, Chantal" sort="Thys, Chantal" uniqKey="Thys C" first="Chantal" last="Thys">Chantal Thys</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Lentaigne, Claire" sort="Lentaigne, Claire" uniqKey="Lentaigne C" first="Claire" last="Lentaigne">Claire Lentaigne</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS</wicri:regionArea><wicri:noRegion>London W12 0HS</wicri:noRegion></affiliation></author><author><name sortKey="Bariana, Tadbir K" sort="Bariana, Tadbir K" uniqKey="Bariana T" first="Tadbir K" last="Bariana">Tadbir K. Bariana</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG</wicri:regionArea><wicri:noRegion>London NW3 2QG</wicri:noRegion></affiliation></author><author><name sortKey="Westbury, Sarah K" sort="Westbury, Sarah K" uniqKey="Westbury S" first="Sarah K" last="Westbury">Sarah K. Westbury</name><affiliation wicri:level="1"><nlm:affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ</wicri:regionArea><wicri:noRegion>Bristol BS2 8DZ</wicri:noRegion></affiliation></author><author><name sortKey="Kelly, Anne M" sort="Kelly, Anne M" uniqKey="Kelly A" first="Anne M" last="Kelly">Anne M. Kelly</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Selleslag, Dominik" sort="Selleslag, Dominik" uniqKey="Selleslag D" first="Dominik" last="Selleslag">Dominik Selleslag</name><affiliation wicri:level="1"><nlm:affiliation>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge</wicri:regionArea><wicri:noRegion>8000 Brugge</wicri:noRegion></affiliation></author><author><name sortKey="Stephens, Jonathan C" sort="Stephens, Jonathan C" uniqKey="Stephens J" first="Jonathan C" last="Stephens">Jonathan C. Stephens</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Papadia, Sofia" sort="Papadia, Sofia" uniqKey="Papadia S" first="Sofia" last="Papadia">Sofia Papadia</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Simeoni, Ilenia" sort="Simeoni, Ilenia" uniqKey="Simeoni I" first="Ilenia" last="Simeoni">Ilenia Simeoni</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Penkett, Christopher J" sort="Penkett, Christopher J" uniqKey="Penkett C" first="Christopher J" last="Penkett">Christopher J. Penkett</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Ashford, Sofie" sort="Ashford, Sofie" uniqKey="Ashford S" first="Sofie" last="Ashford">Sofie Ashford</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Attwood, Antony" sort="Attwood, Antony" uniqKey="Attwood A" first="Antony" last="Attwood">Antony Attwood</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Austin, Steve" sort="Austin, Steve" uniqKey="Austin S" first="Steve" last="Austin">Steve Austin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH</wicri:regionArea><wicri:noRegion>London SE1 7EH</wicri:noRegion></affiliation></author><author><name sortKey="Bakchoul, Tamam" sort="Bakchoul, Tamam" uniqKey="Bakchoul T" first="Tamam" last="Bakchoul">Tamam Bakchoul</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald</wicri:regionArea><wicri:noRegion>17475 Greifswald</wicri:noRegion><wicri:noRegion>17475 Greifswald</wicri:noRegion><wicri:noRegion>17475 Greifswald</wicri:noRegion></affiliation></author><author><name sortKey="Collins, Peter" sort="Collins, Peter" uniqKey="Collins P" first="Peter" last="Collins">Peter Collins</name><affiliation wicri:level="1"><nlm:affiliation>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN</wicri:regionArea><wicri:noRegion>Cardiff CF14 4XN</wicri:noRegion></affiliation></author><author><name sortKey="Deevi, Sri V V" sort="Deevi, Sri V V" uniqKey="Deevi S" first="Sri V V" last="Deevi">Sri V V. Deevi</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Favier, Remi" sort="Favier, Remi" uniqKey="Favier R" first="Rémi" last="Favier">Rémi Favier</name><affiliation wicri:level="1"><nlm:affiliation>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif</wicri:regionArea><wicri:noRegion>94805 Villejuif</wicri:noRegion><wicri:noRegion>94805 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Kostadima, Myrto" sort="Kostadima, Myrto" uniqKey="Kostadima M" first="Myrto" last="Kostadima">Myrto Kostadima</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Lambert, Michele P" sort="Lambert, Michele P" uniqKey="Lambert M" first="Michele P" last="Lambert">Michele P. Lambert</name><affiliation wicri:level="2"><nlm:affiliation>Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Mathias, Mary" sort="Mathias, Mary" uniqKey="Mathias M" first="Mary" last="Mathias">Mary Mathias</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH</wicri:regionArea><wicri:noRegion>London WC1N 3JH</wicri:noRegion></affiliation></author><author><name sortKey="Millar, Carolyn M" sort="Millar, Carolyn M" uniqKey="Millar C" first="Carolyn M" last="Millar">Carolyn M. Millar</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS</wicri:regionArea><wicri:noRegion>London W12 0HS</wicri:noRegion></affiliation></author><author><name sortKey="Peerlinck, Kathelijne" sort="Peerlinck, Kathelijne" uniqKey="Peerlinck K" first="Kathelijne" last="Peerlinck">Kathelijne Peerlinck</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Perry, David J" sort="Perry, David J" uniqKey="Perry D" first="David J" last="Perry">David J. Perry</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QQ</wicri:noRegion></affiliation></author><author><name sortKey="Schulman, Sol" sort="Schulman, Sol" uniqKey="Schulman S" first="Sol" last="Schulman">Sol Schulman</name><affiliation wicri:level="2"><nlm:affiliation>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Whitehorn, Deborah" sort="Whitehorn, Deborah" uniqKey="Whitehorn D" first="Deborah" last="Whitehorn">Deborah Whitehorn</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wittevrongel, Christine" sort="Wittevrongel, Christine" uniqKey="Wittevrongel C" first="Christine" last="Wittevrongel">Christine Wittevrongel</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="De Maeyer, Marc" sort="De Maeyer, Marc" uniqKey="De Maeyer M" first="Marc" last="De Maeyer">Marc De Maeyer</name><affiliation wicri:level="3"><nlm:affiliation>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Rendon, Augusto" sort="Rendon, Augusto" uniqKey="Rendon A" first="Augusto" last="Rendon">Augusto Rendon</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Gomez, Keith" sort="Gomez, Keith" uniqKey="Gomez K" first="Keith" last="Gomez">Keith Gomez</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG</wicri:regionArea><wicri:noRegion>London NW3 2QG</wicri:noRegion></affiliation></author><author><name sortKey="Erber, Wendy N" sort="Erber, Wendy N" uniqKey="Erber W" first="Wendy N" last="Erber">Wendy N. Erber</name><affiliation wicri:level="1"><nlm:affiliation>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009</wicri:regionArea><wicri:noRegion>Western Australia WA 6009</wicri:noRegion></affiliation></author><author><name sortKey="Mumford, Andrew D" sort="Mumford, Andrew D" uniqKey="Mumford A" first="Andrew D" last="Mumford">Andrew D. Mumford</name><affiliation wicri:level="1"><nlm:affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD</wicri:regionArea><wicri:noRegion>Bristol BS8 1TD</wicri:noRegion></affiliation></author><author><name sortKey="Nurden, Paquita" sort="Nurden, Paquita" uniqKey="Nurden P" first="Paquita" last="Nurden">Paquita Nurden</name><affiliation wicri:level="1"><nlm:affiliation>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac</wicri:regionArea><wicri:noRegion>33600 Pessac</wicri:noRegion><wicri:noRegion>33600 Pessac</wicri:noRegion></affiliation></author><author><name sortKey="Stirrups, Kathleen" sort="Stirrups, Kathleen" uniqKey="Stirrups K" first="Kathleen" last="Stirrups">Kathleen Stirrups</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Bradley, John R" sort="Bradley, John R" uniqKey="Bradley J" first="John R" last="Bradley">John R. Bradley</name><affiliation wicri:level="1"><nlm:affiliation>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Research and Development, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Research and Development, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QQ</wicri:noRegion></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F Lucy" last="Raymond">F Lucy Raymond</name><affiliation wicri:level="1"><nlm:affiliation>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY</wicri:regionArea><wicri:noRegion>Cambridge CB2 0XY</wicri:noRegion></affiliation></author><author><name sortKey="Laffan, Michael A" sort="Laffan, Michael A" uniqKey="Laffan M" first="Michael A" last="Laffan">Michael A. Laffan</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS</wicri:regionArea><wicri:noRegion>London W12 0HS</wicri:noRegion></affiliation></author><author><name sortKey="Van Geet, Chris" sort="Van Geet, Chris" uniqKey="Van Geet C" first="Chris" last="Van Geet">Chris Van Geet</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Richardson, Sylvia" sort="Richardson, Sylvia" uniqKey="Richardson S" first="Sylvia" last="Richardson">Sylvia Richardson</name><affiliation wicri:level="1"><nlm:affiliation>Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR</wicri:regionArea><wicri:noRegion>Cambridge CB2 0SR</wicri:noRegion></affiliation></author><author><name sortKey="Freson, Kathleen" sort="Freson, Kathleen" uniqKey="Freson K" first="Kathleen" last="Freson">Kathleen Freson</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. kathleen.freson@med.kuleuven.be.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Ouwehand, Willem H" sort="Ouwehand, Willem H" uniqKey="Ouwehand W" first="Willem H" last="Ouwehand">Willem H. Ouwehand</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26936507</idno><idno type="pmid">26936507</idno><idno type="doi">10.1126/scitranslmed.aad7666</idno><idno type="wicri:Area/PubMed/Corpus">002121</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002121</idno><idno type="wicri:Area/PubMed/Curation">002095</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002095</idno><idno type="wicri:Area/PubMed/Checkpoint">002095</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002095</idno><idno type="wicri:Area/Ncbi/Merge">003219</idno><idno type="wicri:Area/Ncbi/Curation">003219</idno><idno type="wicri:Area/Ncbi/Checkpoint">003219</idno><idno type="wicri:Area/Main/Merge">002470</idno><idno type="wicri:Area/Main/Curation">002471</idno><idno type="wicri:Area/Main/Exploration">002471</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.</title><author><name sortKey="Turro, Ernest" sort="Turro, Ernest" uniqKey="Turro E" first="Ernest" last="Turro">Ernest Turro</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Greene, Daniel" sort="Greene, Daniel" uniqKey="Greene D" first="Daniel" last="Greene">Daniel Greene</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wijgaerts, Anouck" sort="Wijgaerts, Anouck" uniqKey="Wijgaerts A" first="Anouck" last="Wijgaerts">Anouck Wijgaerts</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Thys, Chantal" sort="Thys, Chantal" uniqKey="Thys C" first="Chantal" last="Thys">Chantal Thys</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Lentaigne, Claire" sort="Lentaigne, Claire" uniqKey="Lentaigne C" first="Claire" last="Lentaigne">Claire Lentaigne</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS</wicri:regionArea><wicri:noRegion>London W12 0HS</wicri:noRegion></affiliation></author><author><name sortKey="Bariana, Tadbir K" sort="Bariana, Tadbir K" uniqKey="Bariana T" first="Tadbir K" last="Bariana">Tadbir K. Bariana</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG</wicri:regionArea><wicri:noRegion>London NW3 2QG</wicri:noRegion></affiliation></author><author><name sortKey="Westbury, Sarah K" sort="Westbury, Sarah K" uniqKey="Westbury S" first="Sarah K" last="Westbury">Sarah K. Westbury</name><affiliation wicri:level="1"><nlm:affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ</wicri:regionArea><wicri:noRegion>Bristol BS2 8DZ</wicri:noRegion></affiliation></author><author><name sortKey="Kelly, Anne M" sort="Kelly, Anne M" uniqKey="Kelly A" first="Anne M" last="Kelly">Anne M. Kelly</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Selleslag, Dominik" sort="Selleslag, Dominik" uniqKey="Selleslag D" first="Dominik" last="Selleslag">Dominik Selleslag</name><affiliation wicri:level="1"><nlm:affiliation>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge</wicri:regionArea><wicri:noRegion>8000 Brugge</wicri:noRegion></affiliation></author><author><name sortKey="Stephens, Jonathan C" sort="Stephens, Jonathan C" uniqKey="Stephens J" first="Jonathan C" last="Stephens">Jonathan C. Stephens</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Papadia, Sofia" sort="Papadia, Sofia" uniqKey="Papadia S" first="Sofia" last="Papadia">Sofia Papadia</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Simeoni, Ilenia" sort="Simeoni, Ilenia" uniqKey="Simeoni I" first="Ilenia" last="Simeoni">Ilenia Simeoni</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Penkett, Christopher J" sort="Penkett, Christopher J" uniqKey="Penkett C" first="Christopher J" last="Penkett">Christopher J. Penkett</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Ashford, Sofie" sort="Ashford, Sofie" uniqKey="Ashford S" first="Sofie" last="Ashford">Sofie Ashford</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Attwood, Antony" sort="Attwood, Antony" uniqKey="Attwood A" first="Antony" last="Attwood">Antony Attwood</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Austin, Steve" sort="Austin, Steve" uniqKey="Austin S" first="Steve" last="Austin">Steve Austin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH</wicri:regionArea><wicri:noRegion>London SE1 7EH</wicri:noRegion></affiliation></author><author><name sortKey="Bakchoul, Tamam" sort="Bakchoul, Tamam" uniqKey="Bakchoul T" first="Tamam" last="Bakchoul">Tamam Bakchoul</name><affiliation wicri:level="1"><nlm:affiliation>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald</wicri:regionArea><wicri:noRegion>17475 Greifswald</wicri:noRegion><wicri:noRegion>17475 Greifswald</wicri:noRegion><wicri:noRegion>17475 Greifswald</wicri:noRegion></affiliation></author><author><name sortKey="Collins, Peter" sort="Collins, Peter" uniqKey="Collins P" first="Peter" last="Collins">Peter Collins</name><affiliation wicri:level="1"><nlm:affiliation>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN</wicri:regionArea><wicri:noRegion>Cardiff CF14 4XN</wicri:noRegion></affiliation></author><author><name sortKey="Deevi, Sri V V" sort="Deevi, Sri V V" uniqKey="Deevi S" first="Sri V V" last="Deevi">Sri V V. Deevi</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Favier, Remi" sort="Favier, Remi" uniqKey="Favier R" first="Rémi" last="Favier">Rémi Favier</name><affiliation wicri:level="1"><nlm:affiliation>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif</wicri:regionArea><wicri:noRegion>94805 Villejuif</wicri:noRegion><wicri:noRegion>94805 Villejuif</wicri:noRegion></affiliation></author><author><name sortKey="Kostadima, Myrto" sort="Kostadima, Myrto" uniqKey="Kostadima M" first="Myrto" last="Kostadima">Myrto Kostadima</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Lambert, Michele P" sort="Lambert, Michele P" uniqKey="Lambert M" first="Michele P" last="Lambert">Michele P. Lambert</name><affiliation wicri:level="2"><nlm:affiliation>Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Mathias, Mary" sort="Mathias, Mary" uniqKey="Mathias M" first="Mary" last="Mathias">Mary Mathias</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH</wicri:regionArea><wicri:noRegion>London WC1N 3JH</wicri:noRegion></affiliation></author><author><name sortKey="Millar, Carolyn M" sort="Millar, Carolyn M" uniqKey="Millar C" first="Carolyn M" last="Millar">Carolyn M. Millar</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS</wicri:regionArea><wicri:noRegion>London W12 0HS</wicri:noRegion></affiliation></author><author><name sortKey="Peerlinck, Kathelijne" sort="Peerlinck, Kathelijne" uniqKey="Peerlinck K" first="Kathelijne" last="Peerlinck">Kathelijne Peerlinck</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Perry, David J" sort="Perry, David J" uniqKey="Perry D" first="David J" last="Perry">David J. Perry</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QQ</wicri:noRegion></affiliation></author><author><name sortKey="Schulman, Sol" sort="Schulman, Sol" uniqKey="Schulman S" first="Sol" last="Schulman">Sol Schulman</name><affiliation wicri:level="2"><nlm:affiliation>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Whitehorn, Deborah" sort="Whitehorn, Deborah" uniqKey="Whitehorn D" first="Deborah" last="Whitehorn">Deborah Whitehorn</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wittevrongel, Christine" sort="Wittevrongel, Christine" uniqKey="Wittevrongel C" first="Christine" last="Wittevrongel">Christine Wittevrongel</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="De Maeyer, Marc" sort="De Maeyer, Marc" uniqKey="De Maeyer M" first="Marc" last="De Maeyer">Marc De Maeyer</name><affiliation wicri:level="3"><nlm:affiliation>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="town">Heverlee</settlement><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Rendon, Augusto" sort="Rendon, Augusto" uniqKey="Rendon A" first="Augusto" last="Rendon">Augusto Rendon</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Gomez, Keith" sort="Gomez, Keith" uniqKey="Gomez K" first="Keith" last="Gomez">Keith Gomez</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK. Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London NW3 2QG</wicri:regionArea><wicri:noRegion>London NW3 2QG</wicri:noRegion></affiliation></author><author><name sortKey="Erber, Wendy N" sort="Erber, Wendy N" uniqKey="Erber W" first="Wendy N" last="Erber">Wendy N. Erber</name><affiliation wicri:level="1"><nlm:affiliation>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009</wicri:regionArea><wicri:noRegion>Western Australia WA 6009</wicri:noRegion></affiliation></author><author><name sortKey="Mumford, Andrew D" sort="Mumford, Andrew D" uniqKey="Mumford A" first="Andrew D" last="Mumford">Andrew D. Mumford</name><affiliation wicri:level="1"><nlm:affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD</wicri:regionArea><wicri:noRegion>Bristol BS8 1TD</wicri:noRegion></affiliation></author><author><name sortKey="Nurden, Paquita" sort="Nurden, Paquita" uniqKey="Nurden P" first="Paquita" last="Nurden">Paquita Nurden</name><affiliation wicri:level="1"><nlm:affiliation>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac</wicri:regionArea><wicri:noRegion>33600 Pessac</wicri:noRegion><wicri:noRegion>33600 Pessac</wicri:noRegion></affiliation></author><author><name sortKey="Stirrups, Kathleen" sort="Stirrups, Kathleen" uniqKey="Stirrups K" first="Kathleen" last="Stirrups">Kathleen Stirrups</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Bradley, John R" sort="Bradley, John R" uniqKey="Bradley J" first="John R" last="Bradley">John R. Bradley</name><affiliation wicri:level="1"><nlm:affiliation>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Research and Development, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Research and Development, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ</wicri:regionArea><wicri:noRegion>Cambridge CB2 0QQ</wicri:noRegion></affiliation></author><author><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F Lucy" last="Raymond">F Lucy Raymond</name><affiliation wicri:level="1"><nlm:affiliation>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY</wicri:regionArea><wicri:noRegion>Cambridge CB2 0XY</wicri:noRegion></affiliation></author><author><name sortKey="Laffan, Michael A" sort="Laffan, Michael A" uniqKey="Laffan M" first="Michael A" last="Laffan">Michael A. Laffan</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS</wicri:regionArea><wicri:noRegion>London W12 0HS</wicri:noRegion></affiliation></author><author><name sortKey="Van Geet, Chris" sort="Van Geet, Chris" uniqKey="Van Geet C" first="Chris" last="Van Geet">Chris Van Geet</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Richardson, Sylvia" sort="Richardson, Sylvia" uniqKey="Richardson S" first="Sylvia" last="Richardson">Sylvia Richardson</name><affiliation wicri:level="1"><nlm:affiliation>Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR</wicri:regionArea><wicri:noRegion>Cambridge CB2 0SR</wicri:noRegion></affiliation></author><author><name sortKey="Freson, Kathleen" sort="Freson, Kathleen" uniqKey="Freson K" first="Kathleen" last="Freson">Kathleen Freson</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. kathleen.freson@med.kuleuven.be.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven</wicri:regionArea><placeName><region type="province" nuts="2">Province du Brabant flamand</region><settlement type="city">Louvain</settlement></placeName></affiliation></author><author><name sortKey="Ouwehand, Willem H" sort="Ouwehand, Willem H" uniqKey="Ouwehand W" first="Willem H" last="Ouwehand">Willem H. Ouwehand</name><affiliation wicri:level="4"><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Blood Platelets (pathology)</term><term>Bone and Bones (pathology)</term><term>COS Cells</term><term>Cercopithecus aethiops</term><term>Female</term><term>Hematopoiesis</term><term>Hemorrhage (complications)</term><term>Hemorrhage (genetics)</term><term>Humans</term><term>Male</term><term>Mutation (genetics)</term><term>Pedigree</term><term>Phenotype</term><term>Primary Myelofibrosis (complications)</term><term>Primary Myelofibrosis (genetics)</term><term>Thrombocytopenia (complications)</term><term>Thrombocytopenia (genetics)</term><term>Transfection</term><term>Zebrafish</term><term>src-Family Kinases (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules COS</term><term>Cercopithecus aethiops</term><term>Danio zébré</term><term>Femelle</term><term>Humains</term><term>Hématopoïèse</term><term>Hémorragie ()</term><term>Hémorragie (génétique)</term><term>Mutation (génétique)</term><term>Myélofibrose primitive ()</term><term>Myélofibrose primitive (génétique)</term><term>Mâle</term><term>Os et tissu osseux (anatomopathologie)</term><term>Pedigree</term><term>Phénotype</term><term>Plaquettes (anatomopathologie)</term><term>Thrombopénie ()</term><term>Thrombopénie (génétique)</term><term>Transfection</term><term>src-Family kinases (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>src-Family Kinases</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Os et tissu osseux</term><term>Plaquettes</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Hemorrhage</term><term>Primary Myelofibrosis</term><term>Thrombocytopenia</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Hemorrhage</term><term>Mutation</term><term>Primary Myelofibrosis</term><term>Thrombocytopenia</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Hémorragie</term><term>Mutation</term><term>Myélofibrose primitive</term><term>Thrombopénie</term><term>src-Family kinases</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Blood Platelets</term><term>Bone and Bones</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>COS Cells</term><term>Cercopithecus aethiops</term><term>Female</term><term>Hematopoiesis</term><term>Humans</term><term>Male</term><term>Pedigree</term><term>Phenotype</term><term>Transfection</term><term>Zebrafish</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules COS</term><term>Cercopithecus aethiops</term><term>Danio zébré</term><term>Femelle</term><term>Humains</term><term>Hématopoïèse</term><term>Hémorragie</term><term>Myélofibrose primitive</term><term>Mâle</term><term>Pedigree</term><term>Phénotype</term><term>Thrombopénie</term><term>Transfection</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Belgique</li><li>France</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li><li>Massachusetts</li><li>Pennsylvanie</li><li>Province du Brabant flamand</li></region><settlement><li>Cambridge</li><li>Heverlee</li><li>Louvain</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Turro, Ernest" sort="Turro, Ernest" uniqKey="Turro E" first="Ernest" last="Turro">Ernest Turro</name></region><name sortKey="Ashford, Sofie" sort="Ashford, Sofie" uniqKey="Ashford S" first="Sofie" last="Ashford">Sofie Ashford</name><name sortKey="Attwood, Antony" sort="Attwood, Antony" uniqKey="Attwood A" first="Antony" last="Attwood">Antony Attwood</name><name sortKey="Austin, Steve" sort="Austin, Steve" uniqKey="Austin S" first="Steve" last="Austin">Steve Austin</name><name sortKey="Bariana, Tadbir K" sort="Bariana, Tadbir K" uniqKey="Bariana T" first="Tadbir K" last="Bariana">Tadbir K. Bariana</name><name sortKey="Bradley, John R" sort="Bradley, John R" uniqKey="Bradley J" first="John R" last="Bradley">John R. Bradley</name><name sortKey="Collins, Peter" sort="Collins, Peter" uniqKey="Collins P" first="Peter" last="Collins">Peter Collins</name><name sortKey="Deevi, Sri V V" sort="Deevi, Sri V V" uniqKey="Deevi S" first="Sri V V" last="Deevi">Sri V V. Deevi</name><name sortKey="Gomez, Keith" sort="Gomez, Keith" uniqKey="Gomez K" first="Keith" last="Gomez">Keith Gomez</name><name sortKey="Greene, Daniel" sort="Greene, Daniel" uniqKey="Greene D" first="Daniel" last="Greene">Daniel Greene</name><name sortKey="Kelly, Anne M" sort="Kelly, Anne M" uniqKey="Kelly A" first="Anne M" last="Kelly">Anne M. Kelly</name><name sortKey="Kostadima, Myrto" sort="Kostadima, Myrto" uniqKey="Kostadima M" first="Myrto" last="Kostadima">Myrto Kostadima</name><name sortKey="Laffan, Michael A" sort="Laffan, Michael A" uniqKey="Laffan M" first="Michael A" last="Laffan">Michael A. Laffan</name><name sortKey="Lentaigne, Claire" sort="Lentaigne, Claire" uniqKey="Lentaigne C" first="Claire" last="Lentaigne">Claire Lentaigne</name><name sortKey="Mathias, Mary" sort="Mathias, Mary" uniqKey="Mathias M" first="Mary" last="Mathias">Mary Mathias</name><name sortKey="Millar, Carolyn M" sort="Millar, Carolyn M" uniqKey="Millar C" first="Carolyn M" last="Millar">Carolyn M. Millar</name><name sortKey="Mumford, Andrew D" sort="Mumford, Andrew D" uniqKey="Mumford A" first="Andrew D" last="Mumford">Andrew D. Mumford</name><name sortKey="Ouwehand, Willem H" sort="Ouwehand, Willem H" uniqKey="Ouwehand W" first="Willem H" last="Ouwehand">Willem H. Ouwehand</name><name sortKey="Papadia, Sofia" sort="Papadia, Sofia" uniqKey="Papadia S" first="Sofia" last="Papadia">Sofia Papadia</name><name sortKey="Penkett, Christopher J" sort="Penkett, Christopher J" uniqKey="Penkett C" first="Christopher J" last="Penkett">Christopher J. Penkett</name><name sortKey="Perry, David J" sort="Perry, David J" uniqKey="Perry D" first="David J" last="Perry">David J. Perry</name><name sortKey="Raymond, F Lucy" sort="Raymond, F Lucy" uniqKey="Raymond F" first="F Lucy" last="Raymond">F Lucy Raymond</name><name sortKey="Rendon, Augusto" sort="Rendon, Augusto" uniqKey="Rendon A" first="Augusto" last="Rendon">Augusto Rendon</name><name sortKey="Richardson, Sylvia" sort="Richardson, Sylvia" uniqKey="Richardson S" first="Sylvia" last="Richardson">Sylvia Richardson</name><name sortKey="Simeoni, Ilenia" sort="Simeoni, Ilenia" uniqKey="Simeoni I" first="Ilenia" last="Simeoni">Ilenia Simeoni</name><name sortKey="Stephens, Jonathan C" sort="Stephens, Jonathan C" uniqKey="Stephens J" first="Jonathan C" last="Stephens">Jonathan C. Stephens</name><name sortKey="Stirrups, Kathleen" sort="Stirrups, Kathleen" uniqKey="Stirrups K" first="Kathleen" last="Stirrups">Kathleen Stirrups</name><name sortKey="Westbury, Sarah K" sort="Westbury, Sarah K" uniqKey="Westbury S" first="Sarah K" last="Westbury">Sarah K. Westbury</name><name sortKey="Whitehorn, Deborah" sort="Whitehorn, Deborah" uniqKey="Whitehorn D" first="Deborah" last="Whitehorn">Deborah Whitehorn</name></country><country name="Belgique"><region name="Province du Brabant flamand"><name sortKey="Wijgaerts, Anouck" sort="Wijgaerts, Anouck" uniqKey="Wijgaerts A" first="Anouck" last="Wijgaerts">Anouck Wijgaerts</name></region><name sortKey="De Maeyer, Marc" sort="De Maeyer, Marc" uniqKey="De Maeyer M" first="Marc" last="De Maeyer">Marc De Maeyer</name><name sortKey="Freson, Kathleen" sort="Freson, Kathleen" uniqKey="Freson K" first="Kathleen" last="Freson">Kathleen Freson</name><name sortKey="Peerlinck, Kathelijne" sort="Peerlinck, Kathelijne" uniqKey="Peerlinck K" first="Kathelijne" last="Peerlinck">Kathelijne Peerlinck</name><name sortKey="Selleslag, Dominik" sort="Selleslag, Dominik" uniqKey="Selleslag D" first="Dominik" last="Selleslag">Dominik Selleslag</name><name sortKey="Thys, Chantal" sort="Thys, Chantal" uniqKey="Thys C" first="Chantal" last="Thys">Chantal Thys</name><name sortKey="Van Geet, Chris" sort="Van Geet, Chris" uniqKey="Van Geet C" first="Chris" last="Van Geet">Chris Van Geet</name><name sortKey="Wittevrongel, Christine" sort="Wittevrongel, Christine" uniqKey="Wittevrongel C" first="Christine" last="Wittevrongel">Christine Wittevrongel</name></country><country name="Allemagne"><noRegion><name sortKey="Bakchoul, Tamam" sort="Bakchoul, Tamam" uniqKey="Bakchoul T" first="Tamam" last="Bakchoul">Tamam Bakchoul</name></noRegion></country><country name="France"><noRegion><name sortKey="Favier, Remi" sort="Favier, Remi" uniqKey="Favier R" first="Rémi" last="Favier">Rémi Favier</name></noRegion><name sortKey="Nurden, Paquita" sort="Nurden, Paquita" uniqKey="Nurden P" first="Paquita" last="Nurden">Paquita Nurden</name></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Lambert, Michele P" sort="Lambert, Michele P" uniqKey="Lambert M" first="Michele P" last="Lambert">Michele P. Lambert</name></region><name sortKey="Schulman, Sol" sort="Schulman, Sol" uniqKey="Schulman S" first="Sol" last="Schulman">Sol Schulman</name></country><country name="Australie"><noRegion><name sortKey="Erber, Wendy N" sort="Erber, Wendy N" uniqKey="Erber W" first="Wendy N" last="Erber">Wendy N. Erber</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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