A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies

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 FavierMyrto Kostadima, Michele P Lambert, Mary Mathias, Carolyn M Millar, Kathelijne Peerlinck, David J Perry, Sol Schulman, Deborah Whitehorn, Christine Wittevrongel, BRIDGE-BPD Consortium, 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 Ouwehand

Research output: Contribution to journalArticle (Academic Journal)peer-review

58 Citations (Scopus)
358 Downloads (Pure)

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.
Original languageEnglish
Article number328ra30
JournalScience Translational Medicine
Volume8
Issue number328
DOIs
Publication statusPublished - 2 Mar 2016

Fingerprint Dive into the research topics of 'A dominant gain-of-function mutation in universal tyrosine kinase <i>SRC </i>causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies'. Together they form a unique fingerprint.

Cite this