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A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies
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Dominant SRC gain of function variant _ArticleContent submit.pdf | Accepted version | 18.29 MB | Adobe PDF | View/Open |
Title: | A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies |
Authors: | Turro, E Greene, D Wijgaerts, A Thys, C Lentaigne, C Bariana, TK Westbury, SK Kelly, AM Selleslag, D Stephens, JC Papadia, S Simeoni, I Penkett, CJ Ashford, S Attwood, A Austin, S Bakchoul, T Collins, P Deevi, SVV Favier, R Kostadima, M Lambert, MP Mathias, M Millar, CM Peerlinck, K Perry, DJ Schulman, S Whitehorn, D Wittevrongel, C De Maeyer, M Rendon, A Gomez, K Erber, WN Mumford, AD Nurden, P Stirrups, K Bradley, JR Raymond, FL Laffan, MA Van Geet, C Richardson, S Freson, K Ouwehand, WH |
Item Type: | Journal Article |
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 Tyr419 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. |
Issue Date: | 2-Mar-2016 |
Date of Acceptance: | 21-Jan-2016 |
URI: | http://hdl.handle.net/10044/1/54505 |
DOI: | 10.1126/scitranslmed.aad7666 |
ISSN: | 1946-6234 |
Publisher: | American Association for the Advancement of Science |
Journal / Book Title: | Science Translational Medicine |
Volume: | 8 |
Issue: | 328 |
Copyright Statement: | Copyright © 2016, Copyright © 2016, American Association for the Advancement of Science |
Sponsor/Funder: | Medical Research Council (MRC) |
Funder's Grant Number: | MR/J011711/1 |
Keywords: | Science & Technology Life Sciences & Biomedicine Cell Biology Medicine, Research & Experimental Research & Experimental Medicine HUMAN PHENOTYPE ONTOLOGY GRAY PLATELET SYNDROME PODOSOMES CELLS ZEBRAFISH COMPLEX MATRIX DEFECT MICE RNA Science & Technology Life Sciences & Biomedicine Cell Biology Medicine, Research & Experimental Research & Experimental Medicine HUMAN PHENOTYPE ONTOLOGY PLATELET PODOSOMES MATRIX MEGAKARYOCYTES OSTEOPETROSIS CONFORMATION OSTEOCLASTS IMATINIB UNRAVEL Animals Blood Platelets Bone and Bones COS Cells Chlorocebus aethiops Female Hematopoiesis Hemorrhage Humans Male Mutation Pedigree Phenotype Primary Myelofibrosis Thrombocytopenia Transfection Zebrafish src-Family Kinases BRIDGE-BPD Consortium Bone and Bones Blood Platelets COS Cells Animals Zebrafish Humans Thrombocytopenia Hemorrhage src-Family Kinases Transfection Pedigree Hematopoiesis Phenotype Mutation Female Male Primary Myelofibrosis Chlorocebus aethiops 06 Biological Sciences 11 Medical and Health Sciences |
Publication Status: | Published |
Article Number: | ARTN 328ra30 |
Appears in Collections: | Department of Immunology and Inflammation Faculty of Medicine |