A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.
Identifieur interne : 002121 ( PubMed/Corpus ); précédent : 002120; suivant : 002122A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.
Auteurs : Ernest Turro ; Daniel Greene ; Anouck Wijgaerts ; Chantal Thys ; Claire Lentaigne ; Tadbir K. Bariana ; Sarah K. Westbury ; Anne M. Kelly ; Dominik Selleslag ; Jonathan C. Stephens ; Sofia Papadia ; Ilenia Simeoni ; Christopher J. Penkett ; Sofie Ashford ; Antony Attwood ; Steve Austin ; Tamam Bakchoul ; Peter Collins ; Sri V V. Deevi ; Rémi Favier ; Myrto Kostadima ; Michele P. Lambert ; Mary Mathias ; Carolyn M. Millar ; Kathelijne Peerlinck ; David J. Perry ; Sol Schulman ; Deborah Whitehorn ; Christine Wittevrongel ; Marc De Maeyer ; Augusto Rendon ; Keith Gomez ; Wendy N. Erber ; Andrew D. Mumford ; Paquita Nurden ; Kathleen Stirrups ; John R. Bradley ; F Lucy Raymond ; Michael A. Laffan ; Chris Van Geet ; Sylvia Richardson ; Kathleen Freson ; Willem H. OuwehandSource :
- Science translational medicine [ 1946-6242 ] ; 2016.
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
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pubmed:26936507Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><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><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></affiliation></author><author><name sortKey="Greene, Daniel" sort="Greene, Daniel" uniqKey="Greene D" first="Daniel" last="Greene">Daniel Greene</name><affiliation><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></affiliation></author><author><name sortKey="Wijgaerts, Anouck" sort="Wijgaerts, Anouck" uniqKey="Wijgaerts A" first="Anouck" last="Wijgaerts">Anouck Wijgaerts</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Thys, Chantal" sort="Thys, Chantal" uniqKey="Thys C" first="Chantal" last="Thys">Chantal Thys</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Lentaigne, Claire" sort="Lentaigne, Claire" uniqKey="Lentaigne C" first="Claire" last="Lentaigne">Claire Lentaigne</name><affiliation><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></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><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></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><nlm:affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Selleslag, Dominik" sort="Selleslag, Dominik" uniqKey="Selleslag D" first="Dominik" last="Selleslag">Dominik Selleslag</name><affiliation><nlm:affiliation>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge, Belgium.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Papadia, Sofia" sort="Papadia, Sofia" uniqKey="Papadia S" first="Sofia" last="Papadia">Sofia Papadia</name><affiliation><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></affiliation></author><author><name sortKey="Simeoni, Ilenia" sort="Simeoni, Ilenia" uniqKey="Simeoni I" first="Ilenia" last="Simeoni">Ilenia Simeoni</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Ashford, Sofie" sort="Ashford, Sofie" uniqKey="Ashford S" first="Sofie" last="Ashford">Sofie Ashford</name><affiliation><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></affiliation></author><author><name sortKey="Attwood, Antony" sort="Attwood, Antony" uniqKey="Attwood A" first="Antony" last="Attwood">Antony Attwood</name><affiliation><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></affiliation></author><author><name sortKey="Austin, Steve" sort="Austin, Steve" uniqKey="Austin S" first="Steve" last="Austin">Steve Austin</name><affiliation><nlm:affiliation>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bakchoul, Tamam" sort="Bakchoul, Tamam" uniqKey="Bakchoul T" first="Tamam" last="Bakchoul">Tamam Bakchoul</name><affiliation><nlm:affiliation>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Collins, Peter" sort="Collins, Peter" uniqKey="Collins P" first="Peter" last="Collins">Peter Collins</name><affiliation><nlm:affiliation>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Favier, Remi" sort="Favier, Remi" uniqKey="Favier R" first="Rémi" last="Favier">Rémi Favier</name><affiliation><nlm:affiliation>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif, France.</nlm:affiliation></affiliation></author><author><name sortKey="Kostadima, Myrto" sort="Kostadima, Myrto" uniqKey="Kostadima M" first="Myrto" last="Kostadima">Myrto Kostadima</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Mathias, Mary" sort="Mathias, Mary" uniqKey="Mathias M" first="Mary" last="Mathias">Mary Mathias</name><affiliation><nlm:affiliation>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Peerlinck, Kathelijne" sort="Peerlinck, Kathelijne" uniqKey="Peerlinck K" first="Kathelijne" last="Peerlinck">Kathelijne Peerlinck</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></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><nlm:affiliation>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Schulman, Sol" sort="Schulman, Sol" uniqKey="Schulman S" first="Sol" last="Schulman">Sol Schulman</name><affiliation><nlm:affiliation>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Whitehorn, Deborah" sort="Whitehorn, Deborah" uniqKey="Whitehorn D" first="Deborah" last="Whitehorn">Deborah Whitehorn</name><affiliation><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></affiliation></author><author><name sortKey="Wittevrongel, Christine" sort="Wittevrongel, Christine" uniqKey="Wittevrongel C" first="Christine" last="Wittevrongel">Christine Wittevrongel</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></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><nlm:affiliation>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Rendon, Augusto" sort="Rendon, Augusto" uniqKey="Rendon A" first="Augusto" last="Rendon">Augusto Rendon</name><affiliation><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Gomez, Keith" sort="Gomez, Keith" uniqKey="Gomez K" first="Keith" last="Gomez">Keith Gomez</name><affiliation><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></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><nlm:affiliation>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009, Australia.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Nurden, Paquita" sort="Nurden, Paquita" uniqKey="Nurden P" first="Paquita" last="Nurden">Paquita Nurden</name><affiliation><nlm:affiliation>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac, France.</nlm:affiliation></affiliation></author><author><name sortKey="Stirrups, Kathleen" sort="Stirrups, Kathleen" uniqKey="Stirrups K" first="Kathleen" last="Stirrups">Kathleen Stirrups</name><affiliation><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></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><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></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><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></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><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></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><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Richardson, Sylvia" sort="Richardson, Sylvia" uniqKey="Richardson S" first="Sylvia" last="Richardson">Sylvia Richardson</name><affiliation><nlm:affiliation>Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Freson, Kathleen" sort="Freson, Kathleen" uniqKey="Freson K" first="Kathleen" last="Freson">Kathleen Freson</name><affiliation><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></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><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></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></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><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></affiliation></author><author><name sortKey="Greene, Daniel" sort="Greene, Daniel" uniqKey="Greene D" first="Daniel" last="Greene">Daniel Greene</name><affiliation><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></affiliation></author><author><name sortKey="Wijgaerts, Anouck" sort="Wijgaerts, Anouck" uniqKey="Wijgaerts A" first="Anouck" last="Wijgaerts">Anouck Wijgaerts</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Thys, Chantal" sort="Thys, Chantal" uniqKey="Thys C" first="Chantal" last="Thys">Chantal Thys</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Lentaigne, Claire" sort="Lentaigne, Claire" uniqKey="Lentaigne C" first="Claire" last="Lentaigne">Claire Lentaigne</name><affiliation><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></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><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></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><nlm:affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Selleslag, Dominik" sort="Selleslag, Dominik" uniqKey="Selleslag D" first="Dominik" last="Selleslag">Dominik Selleslag</name><affiliation><nlm:affiliation>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge, Belgium.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Papadia, Sofia" sort="Papadia, Sofia" uniqKey="Papadia S" first="Sofia" last="Papadia">Sofia Papadia</name><affiliation><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></affiliation></author><author><name sortKey="Simeoni, Ilenia" sort="Simeoni, Ilenia" uniqKey="Simeoni I" first="Ilenia" last="Simeoni">Ilenia Simeoni</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Ashford, Sofie" sort="Ashford, Sofie" uniqKey="Ashford S" first="Sofie" last="Ashford">Sofie Ashford</name><affiliation><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></affiliation></author><author><name sortKey="Attwood, Antony" sort="Attwood, Antony" uniqKey="Attwood A" first="Antony" last="Attwood">Antony Attwood</name><affiliation><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></affiliation></author><author><name sortKey="Austin, Steve" sort="Austin, Steve" uniqKey="Austin S" first="Steve" last="Austin">Steve Austin</name><affiliation><nlm:affiliation>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Bakchoul, Tamam" sort="Bakchoul, Tamam" uniqKey="Bakchoul T" first="Tamam" last="Bakchoul">Tamam Bakchoul</name><affiliation><nlm:affiliation>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Collins, Peter" sort="Collins, Peter" uniqKey="Collins P" first="Peter" last="Collins">Peter Collins</name><affiliation><nlm:affiliation>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Favier, Remi" sort="Favier, Remi" uniqKey="Favier R" first="Rémi" last="Favier">Rémi Favier</name><affiliation><nlm:affiliation>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif, France.</nlm:affiliation></affiliation></author><author><name sortKey="Kostadima, Myrto" sort="Kostadima, Myrto" uniqKey="Kostadima M" first="Myrto" last="Kostadima">Myrto Kostadima</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Mathias, Mary" sort="Mathias, Mary" uniqKey="Mathias M" first="Mary" last="Mathias">Mary Mathias</name><affiliation><nlm:affiliation>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Peerlinck, Kathelijne" sort="Peerlinck, Kathelijne" uniqKey="Peerlinck K" first="Kathelijne" last="Peerlinck">Kathelijne Peerlinck</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></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><nlm:affiliation>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Schulman, Sol" sort="Schulman, Sol" uniqKey="Schulman S" first="Sol" last="Schulman">Sol Schulman</name><affiliation><nlm:affiliation>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Whitehorn, Deborah" sort="Whitehorn, Deborah" uniqKey="Whitehorn D" first="Deborah" last="Whitehorn">Deborah Whitehorn</name><affiliation><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></affiliation></author><author><name sortKey="Wittevrongel, Christine" sort="Wittevrongel, Christine" uniqKey="Wittevrongel C" first="Christine" last="Wittevrongel">Christine Wittevrongel</name><affiliation><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></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><nlm:affiliation>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Rendon, Augusto" sort="Rendon, Augusto" uniqKey="Rendon A" first="Augusto" last="Rendon">Augusto Rendon</name><affiliation><nlm:affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Gomez, Keith" sort="Gomez, Keith" uniqKey="Gomez K" first="Keith" last="Gomez">Keith Gomez</name><affiliation><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></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><nlm:affiliation>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009, Australia.</nlm:affiliation></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><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></affiliation></author><author><name sortKey="Nurden, Paquita" sort="Nurden, Paquita" uniqKey="Nurden P" first="Paquita" last="Nurden">Paquita Nurden</name><affiliation><nlm:affiliation>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac, France.</nlm:affiliation></affiliation></author><author><name sortKey="Stirrups, Kathleen" sort="Stirrups, Kathleen" uniqKey="Stirrups K" first="Kathleen" last="Stirrups">Kathleen Stirrups</name><affiliation><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></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><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></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><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></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><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></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><nlm:affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</nlm:affiliation></affiliation></author><author><name sortKey="Richardson, Sylvia" sort="Richardson, Sylvia" uniqKey="Richardson S" first="Sylvia" last="Richardson">Sylvia Richardson</name><affiliation><nlm:affiliation>Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Freson, Kathleen" sort="Freson, Kathleen" uniqKey="Freson K" first="Kathleen" last="Freson">Kathleen Freson</name><affiliation><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></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><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></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="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>src-Family Kinases</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="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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26936507</PMID><DateCreated><Year>2016</Year><Month>03</Month><Day>03</Day></DateCreated><DateCompleted><Year>2016</Year><Month>12</Month><Day>13</Day></DateCompleted><DateRevised><Year>2017</Year><Month>11</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1946-6242</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>328</Issue><PubDate><Year>2016</Year><Month>Mar</Month><Day>02</Day></PubDate></JournalIssue><Title>Science translational medicine</Title><ISOAbbreviation>Sci Transl Med</ISOAbbreviation></Journal><ArticleTitle>A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.</ArticleTitle><Pagination><MedlinePgn>328ra30</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1126/scitranslmed.aad7666</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>Copyright © 2016, American Association for the Advancement of Science.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Turro</LastName><ForeName>Ernest</ForeName><Initials>E</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Greene</LastName><ForeName>Daniel</ForeName><Initials>D</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wijgaerts</LastName><ForeName>Anouck</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thys</LastName><ForeName>Chantal</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lentaigne</LastName><ForeName>Claire</ForeName><Initials>C</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bariana</LastName><ForeName>Tadbir K</ForeName><Initials>TK</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Westbury</LastName><ForeName>Sarah K</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kelly</LastName><ForeName>Anne M</ForeName><Initials>AM</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Selleslag</LastName><ForeName>Dominik</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Academisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stephens</LastName><ForeName>Jonathan C</ForeName><Initials>JC</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Papadia</LastName><ForeName>Sofia</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Simeoni</LastName><ForeName>Ilenia</ForeName><Initials>I</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Penkett</LastName><ForeName>Christopher J</ForeName><Initials>CJ</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ashford</LastName><ForeName>Sofie</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Attwood</LastName><ForeName>Antony</ForeName><Initials>A</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Austin</LastName><ForeName>Steve</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bakchoul</LastName><ForeName>Tamam</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Collins</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Deevi</LastName><ForeName>Sri V V</ForeName><Initials>SV</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Favier</LastName><ForeName>Rémi</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kostadima</LastName><ForeName>Myrto</ForeName><Initials>M</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lambert</LastName><ForeName>Michele P</ForeName><Initials>MP</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mathias</LastName><ForeName>Mary</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Millar</LastName><ForeName>Carolyn M</ForeName><Initials>CM</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peerlinck</LastName><ForeName>Kathelijne</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Perry</LastName><ForeName>David J</ForeName><Initials>DJ</Initials><AffiliationInfo><Affiliation>Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schulman</LastName><ForeName>Sol</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Whitehorn</LastName><ForeName>Deborah</ForeName><Initials>D</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wittevrongel</LastName><ForeName>Christine</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><CollectiveName>BRIDGE-BPD Consortium</CollectiveName></Author><Author ValidYN="Y"><LastName>De Maeyer</LastName><ForeName>Marc</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rendon</LastName><ForeName>Augusto</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gomez</LastName><ForeName>Keith</ForeName><Initials>K</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Erber</LastName><ForeName>Wendy N</ForeName><Initials>WN</Initials><AffiliationInfo><Affiliation>Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mumford</LastName><ForeName>Andrew D</ForeName><Initials>AD</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nurden</LastName><ForeName>Paquita</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Institut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stirrups</LastName><ForeName>Kathleen</ForeName><Initials>K</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bradley</LastName><ForeName>John R</ForeName><Initials>JR</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Raymond</LastName><ForeName>F Lucy</ForeName><Initials>FL</Initials><AffiliationInfo><Affiliation>National Institute for Health Research (NIHR) BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. 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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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>RP-PG-0310-1002</GrantID><Agency>Department of Health</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MR/K023489/1</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>RG/09/12/28096</GrantID><Agency>British Heart Foundation</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>U54 HL112311</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>MC_UP_0801/1</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>MR/J011711/1</GrantID><Agency>Medical Research Council</Agency><Country>United 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ValidYN="Y"><LastName>Roughley</LastName><ForeName>Catherine</ForeName><Initials>C</Initials></Investigator><Investigator ValidYN="Y"><LastName>Schulze</LastName><ForeName>Harald</ForeName><Initials>H</Initials></Investigator><Investigator ValidYN="Y"><LastName>Talks</LastName><ForeName>Kate</ForeName><Initials>K</Initials></Investigator><Investigator ValidYN="Y"><LastName>Thachil</LastName><ForeName>Jecko</ForeName><Initials>J</Initials></Investigator><Investigator ValidYN="Y"><LastName>Toh</LastName><ForeName>Cheng-Hock</ForeName><Initials>CH</Initials></Investigator></InvestigatorList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>10</Month><Day>28</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>01</Month><Day>21</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>3</Month><Day>4</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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