Publication: Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice
Authors
Guerrero López, José Antonio ; Bennett, Cavan ; Weyden, Louise van der ; McKinney, Harriet ; Chin, Melody ; Nurden, Paquita ; McIntyre, Zoe ; Cambridge, Emma L. ; Estabel, Jeanne ; Wardle Jones, Hannah ; Speak, Anneliese O. ; Erber, Wendy N. ; Rendon, Augusto ; Ouwehand, Willem H. ; Ghevaer, Cedric
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Publisher
American Society of Hematology (ASH Publications)
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DOI
https://doi.org/10.1182/blood-2014-04-566760
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info:eu-repo/semantics/article
Description
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.
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Citation
Blood, Volume 124, Issue 24, 4 December 2014, Pages 3624-3635
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