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;
Blood. 2014 Dec 4;124(24):3624-35. doi: 10.1182/blood-2014-04-566760. Epub 2014 Sep 25.
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.
NBEAL2 编码一种具有多结构域支架蛋白，可能在人类血小板颗粒发生中发挥作用。NBEAL2 突变是灰色血小板综合征 (GPS) 的基础，GPS 是一种罕见的遗传性出血性疾病，其特征是血小板内缺乏 α-颗粒和进行性骨髓纤维化。我们在此介绍了一种新型 GPS 的 Nbeal2(-/-) 小鼠模型，并证明 α-颗粒的缺乏是由于它们从血小板/成熟巨核细胞 (MK) 中丢失，而不是由于初始形成受损。我们表明，缺乏 Nbeal2 赋予骨髓 MK 以促炎表型，这与 α-颗粒中蛋白质的丢失相结合，导致骨髓纤维化的发展。此外，我们证明 α-颗粒缺乏不仅会损害血小板的止血作用，还会损害其功能，并且 Nbeal2 缺乏对癌症转移具有保护作用。
