Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice

J.A. Guerrero, C. Bennett, L. Van Der Weyden, H. Mckinney, M. Chin, P. Nurden, Z. Mcintyre, E.L. Cambridge, J. Estabel, H. Wardle-Jones, A.O. Speak, Wendy Erber, A. Rendon, W.H. Ouwehand, C.J.G. Ghevaert

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

© 2014 by The American Society of Hematology. 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.
Original languageEnglish
Pages (from-to)3624-3635
JournalBlood
Volume124
Issue number24
DOIs
Publication statusPublished - 2014

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