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


Type

Article

Change log

Authors

Guerrero, Jose A 
Bennett, Cavan 
van der Weyden, Louise 
McKinney, Harriet 
Chin, Melody 

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.

Description

Keywords

Animals, Blood Proteins, Disease Models, Animal, Gray Platelet Syndrome, Humans, Megakaryocytes, Mice, Mice, Knockout, Mutation, Neoplasm Metastasis, Neoplasms, Primary Myelofibrosis, Secretory Vesicles

Journal Title

Blood

Conference Name

Journal ISSN

0006-4971
1528-0020

Volume Title

124

Publisher

American Society of Hematology
Sponsorship
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
This work was funded by the British Heart Foundation to CG (FS09/039) and WHO and AR (RG/09/12/28096); NHSBT to CB and HM; Wellcome Trust (WT098051) to ZM, ELC, JE, HWJ and AOS.