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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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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