title: Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice.
abstract: NBEAL2 encodes a multidomain scaffolding protein with a putative role in granule ontogeny in human platelets. Mutations in NBEAL2 underlie gray platelet syndrome (GPS), a rare inherited bleeding disorder characterized by a lack of α-granules within blood platelets and progressive bone marrow fibrosis. We present here a novel Nbeal2(-/-) murine model of GPS and demonstrate that the lack of α-granules is due to their loss from platelets/mature megakaryocytes (MKs), and not by initial impaired formation. We show that the lack of Nbeal2 confers a proinflammatory phenotype to the bone marrow MKs, which in combination with the loss of proteins from α-granules drives the development of bone marrow fibrosis. In addition, we demonstrate that α-granule deficiency impairs platelet function beyond their purely hemostatic role and that Nbeal2 deficiency has a protective effect against cancer metastasis.
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Jose A
authors.initials: JA
authors.lastname: Guerrero
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Cavan
authors.initials: C
authors.lastname: Bennett
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Harriet
authors.initials: H
authors.lastname: McKinney
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Melody
authors.initials: M
authors.lastname: Chin
authors.affiliation: Institut Hospitalo-Universitaire L'Institut de Rythmologie et Modélisation Cardiaque, Hopital Xavier Arnozan, Pessac, France; and.
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Zoe
authors.initials: Z
authors.lastname: McIntyre
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Emma L
authors.initials: EL
authors.lastname: Cambridge
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Jeanne
authors.initials: J
authors.lastname: Estabel
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Hannah
authors.initials: H
authors.lastname: Wardle-Jones
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.affiliation: Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia.
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Augusto
authors.initials: A
authors.lastname: Rendon
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Cedric
authors.initials: C
authors.lastname: Ghevaert
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D055652:Gray Platelet Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022142:Secretory Vesicles
chemical_list: D001798:Blood Proteins; C585423:Nbeal2 protein, mouse