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

JA Guerrero, C Bennett… - Blood, The Journal …, 2014 - ashpublications.org
JA Guerrero, C Bennett, L van der Weyden, H McKinney, M Chin, P Nurden, Z McIntyre…
Blood, The Journal of the American Society of Hematology, 2014ashpublications.org
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 …
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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