ArticleScience translational medicine2016
A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.
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Article in Science translational medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53citing papers in PubMed
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53 citing papers in PubMed, 142 citations in OpenAlex.
- Expanding the Spectrum of Src-Family Kinase-Related Autoinflammatory Diseases: Monogenic Vasculitis Caused By Germline Pathogenic Variants in HCK and FGR.Journal of clinical immunology · 2026Article
- The stress-activated kinase p38 mediates non-canonical activation of Src and tyrosine phosphorylation of the adapter protein TAB1.The Journal of biological chemistry · 2026Article
- Bioinformatics-driven identification of pathogenic missense nsSNPs in the human proto-oncogene SRC and cancer susceptibility.Journal, genetic engineering & biotechnology · 2025Article
- Uncovering the molecular basis of kinase activity and substrate recognition with phospho-PCA.bioRxiv : the preprint server for biology · 2025Article
- Integrating machine learning and structure-based approaches for repurposing potent tyrosine protein kinase Src inhibitors to treat inflammatory disorders.Scientific reports · 2025Article
- Activated Src kinase promotes cell cannibalism in Drosophila.The Journal of cell biology · 2023Article
- Computational prognostic evaluation of Alzheimer's drugs from FDA-approved database through structural conformational dynamics and drug repositioning approaches.Scientific reports · 2023Article
- A Phase Ib Trial of AVID200, a TGFβ 1/3 Trap, in Patients with Myelofibrosis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation.Nature cardiovascular research · 2023Article
- Exome sequencing in 116 patients with inherited thrombocytopenia that remained of unknown origin after systematic phenotype-driven diagnostic workup.Haematologica · 2023Article
- Correspondence between functional scores from deep mutational scans and predicted effects on protein stability.Protein science : a publication of the Protein Society · 2023Article
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- Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome.Nature communications · 2023Article
- CSK-mediated signalling by integrins in cancer.Frontiers in cell and developmental biology · 2023Review
- Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation.Nature communications · 2022Article
- Mapping human disease-associated enzymes into Reactome allows characterization of disease groups and their interactions.Scientific reports · 2022Article
- Src-related thrombocytopenia: a fine line between a megakaryocyte dysfunction and an immune-mediated disease.Blood advances · 2022Article
- Genetics of inherited thrombocytopenias.Blood · 2022Review
- Diagnostic Value of a Protocolized In-Depth Evaluation of Pediatric Bone Marrow Failure: A Multi-Center Prospective Cohort Study.Frontiers in immunology · 2022Article
- Hemostatic phenotypes and genetic disorders.Research and practice in thrombosis and haemostasis · 2021Article
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Authors and funding
44 authors at 11 institutions in 4 countries.
Ernest TurroDepartment 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.
Daniel GreeneDepartment 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.
Anouck WijgaertsDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
Chantal ThysDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
Claire LentaigneCentre 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.
Tadbir K BarianaDepartment 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.
Sarah K WestburySchool of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK.
Anne M KellyDepartment 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.
Dominik SelleslagAcademisch Ziekenhuis Sint-Jan Brugge-Oostende, 8000 Brugge, Belgium.
Jonathan C StephensDepartment 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.
Sofia PapadiaDepartment 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.
Ilenia SimeoniDepartment 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.
Christopher J PenkettDepartment 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.
Sofie AshfordDepartment 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.
Antony AttwoodDepartment 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.
Steve AustinDepartment of Haematology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.
Tamam BakchoulInstitute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
Peter CollinsArthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
Sri V V DeeviDepartment 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.
Rémi FavierAssistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, 75012 Paris, France. INSERM U1170, 94805 Villejuif, France.
Myrto KostadimaDepartment 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.
Michele P LambertDivision 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.
Mary MathiasDepartment of Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
Carolyn M MillarCentre 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.
Kathelijne PeerlinckDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
David J PerryDepartment of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Sol SchulmanBeth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA.
Deborah WhitehornDepartment 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.
Christine WittevrongelDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
BRIDGE-BPD Consortium
Marc De MaeyerBiochemistry, Molecular and Structural Biology Section, University of Leuven, 3001 Leuven, Belgium.
Augusto RendonDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Genomics England Ltd., London EC1M 6BQ, UK.
Keith GomezDepartment 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.
Wendy N ErberPathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia WA 6009, Australia.
Andrew D MumfordSchool of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK.
Paquita NurdenInstitut Hospitalo-Universitaire LIRYC, PTIB, Hôpital Xavier Arnozan, 33600 Pessac, France.
Kathleen StirrupsDepartment 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.
John R BradleyNational 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.
F Lucy RaymondNational 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.
Michael A LaffanCentre 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.
Chris Van GeetDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
Sylvia RichardsonMedical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
Kathleen FresonDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. kathleen.freson@med.kuleuven.be.
Willem H OuwehandDepartment 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.
University of Cambridge · GBKU Leuven · BEImperial College Healthcare NHS Trust · GBNational Health Service · GBUniversity of Bristol · GBGuy's and St Thomas' NHS Foundation Trust · GBHarvard University · USInserm · FRLondon Cancer · GBRoyal Free London NHS Foundation Trust · GBUniversity of Pennsylvania · US
Funding
Translational Research Skills Development CoreU54HL112311 · NHLBI · UNIVERSITY OF UTAH · PI WEYRICH, ANDREW S, ZIMMERMAN, GUY A. · 2012 to 2016
$12.9MThe Effects of ART on Platelets and HIV-Associated ThrombosisR01HL126547 · NHLBI · UNIVERSITY OF UTAH · PI PLANELLES, VICENTE, RONDINA, MATTHEW THOMAS · 2014 to 2017
$3.0MBritish Heart Foundation RG/09/012/28096British Heart Foundation RG/09/12/28096British Heart Foundation RG59534Department of Health RP-PG-0310-1002Medical Research Council MC_UP_0801/1Medical Research Council MC_UU_00002/10Medical Research Council MR/J011711/1Medical Research Council MR/K023489/1NHLBI NIH HHS R01 HL126547NHLBI NIH HHS U54 HL112311
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.
Indexed as
AnimalsBlood PlateletsBone and BonesChlorocebus aethiopsCOS CellsFemaleHematopoiesisHemorrhageHumansMaleMutationPedigreePhenotypePrimary Myelofibrosissrc-Family KinasesThrombocytopeniasrc-Family Kinases
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