A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies
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...
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creator | Turro, Ernest Greene, Daniel Wijgaerts, Anouck Thys, Chantal Lentaigne, Claire Bariana, Tadbir K Westbury, Sarah K Kelly, Anne M Selleslag, Dominik Stephens, Jonathan C Papadia, Sofia Simeoni, Ilenia Penkett, Christopher J Ashford, Sofie Attwood, Antony Austin, Steve Bakchoul, Tamam Collins, Peter Deevi, Sri V.V Favier, Rémi Kostadima, Myrto Lambert, Michele P Mathias, Mary Millar, Carolyn M Peerlinck, Kathelijne Perry, David J Schulman, Sol Whitehorn, Deborah Wittevrongel, Christine De Maeyer, Marc Rendon, Augusto Gomez, Keith Erber, Wendy N Mumford, Andrew D Nurden, Paquita Stirrups, Kathleen Bradley, John R Lucy Raymond, F Laffan, Michael A Van Geet, Chris Richardson, Sylvia Freson, Kathleen Ouwehand, Willem H |
description | 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. |
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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.</description><identifier>ISSN: 1946-6234</identifier><language>eng</language><publisher>AMER ASSOC ADVANCEMENT SCIENCE</publisher><ispartof>Science Translational Medicine, 2016-03, Vol.8 (328), p.328</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,780,27860</link.rule.ids><linktorsrc>$$Uhttps://lirias.kuleuven.be/handle/123456789/533994$$EView_record_in_KU_Leuven_Association$$FView_record_in_$$GKU_Leuven_Association$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>Turro, Ernest</creatorcontrib><creatorcontrib>Greene, Daniel</creatorcontrib><creatorcontrib>Wijgaerts, Anouck</creatorcontrib><creatorcontrib>Thys, Chantal</creatorcontrib><creatorcontrib>Lentaigne, Claire</creatorcontrib><creatorcontrib>Bariana, Tadbir K</creatorcontrib><creatorcontrib>Westbury, Sarah K</creatorcontrib><creatorcontrib>Kelly, Anne M</creatorcontrib><creatorcontrib>Selleslag, Dominik</creatorcontrib><creatorcontrib>Stephens, Jonathan C</creatorcontrib><creatorcontrib>Papadia, Sofia</creatorcontrib><creatorcontrib>Simeoni, Ilenia</creatorcontrib><creatorcontrib>Penkett, Christopher J</creatorcontrib><creatorcontrib>Ashford, Sofie</creatorcontrib><creatorcontrib>Attwood, Antony</creatorcontrib><creatorcontrib>Austin, Steve</creatorcontrib><creatorcontrib>Bakchoul, Tamam</creatorcontrib><creatorcontrib>Collins, Peter</creatorcontrib><creatorcontrib>Deevi, Sri V.V</creatorcontrib><creatorcontrib>Favier, Rémi</creatorcontrib><creatorcontrib>Kostadima, Myrto</creatorcontrib><creatorcontrib>Lambert, Michele P</creatorcontrib><creatorcontrib>Mathias, Mary</creatorcontrib><creatorcontrib>Millar, Carolyn M</creatorcontrib><creatorcontrib>Peerlinck, Kathelijne</creatorcontrib><creatorcontrib>Perry, David J</creatorcontrib><creatorcontrib>Schulman, Sol</creatorcontrib><creatorcontrib>Whitehorn, Deborah</creatorcontrib><creatorcontrib>Wittevrongel, Christine</creatorcontrib><creatorcontrib>De Maeyer, Marc</creatorcontrib><creatorcontrib>Rendon, Augusto</creatorcontrib><creatorcontrib>Gomez, Keith</creatorcontrib><creatorcontrib>Erber, Wendy N</creatorcontrib><creatorcontrib>Mumford, Andrew D</creatorcontrib><creatorcontrib>Nurden, Paquita</creatorcontrib><creatorcontrib>Stirrups, Kathleen</creatorcontrib><creatorcontrib>Bradley, John R</creatorcontrib><creatorcontrib>Lucy Raymond, F</creatorcontrib><creatorcontrib>Laffan, Michael A</creatorcontrib><creatorcontrib>Van Geet, Chris</creatorcontrib><creatorcontrib>Richardson, Sylvia</creatorcontrib><creatorcontrib>Freson, Kathleen</creatorcontrib><creatorcontrib>Ouwehand, Willem H</creatorcontrib><title>A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies</title><title>Science Translational Medicine</title><description>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. 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Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Turro, Ernest</au><au>Greene, Daniel</au><au>Wijgaerts, Anouck</au><au>Thys, Chantal</au><au>Lentaigne, Claire</au><au>Bariana, Tadbir K</au><au>Westbury, Sarah K</au><au>Kelly, Anne M</au><au>Selleslag, Dominik</au><au>Stephens, Jonathan C</au><au>Papadia, Sofia</au><au>Simeoni, Ilenia</au><au>Penkett, Christopher J</au><au>Ashford, Sofie</au><au>Attwood, Antony</au><au>Austin, Steve</au><au>Bakchoul, Tamam</au><au>Collins, Peter</au><au>Deevi, Sri V.V</au><au>Favier, Rémi</au><au>Kostadima, Myrto</au><au>Lambert, Michele P</au><au>Mathias, Mary</au><au>Millar, Carolyn M</au><au>Peerlinck, Kathelijne</au><au>Perry, David J</au><au>Schulman, Sol</au><au>Whitehorn, Deborah</au><au>Wittevrongel, Christine</au><au>De Maeyer, Marc</au><au>Rendon, Augusto</au><au>Gomez, Keith</au><au>Erber, Wendy N</au><au>Mumford, Andrew D</au><au>Nurden, Paquita</au><au>Stirrups, Kathleen</au><au>Bradley, John R</au><au>Lucy Raymond, F</au><au>Laffan, Michael A</au><au>Van Geet, Chris</au><au>Richardson, Sylvia</au><au>Freson, Kathleen</au><au>Ouwehand, Willem H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies</atitle><jtitle>Science Translational Medicine</jtitle><date>2016-03</date><risdate>2016</risdate><volume>8</volume><issue>328</issue><spage>328</spage><pages>328-</pages><issn>1946-6234</issn><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.</abstract><pub>AMER ASSOC ADVANCEMENT SCIENCE</pub><oa>free_for_read</oa></addata></record> |
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title | A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies |
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