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

Guerrero, José Antonio López; 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.; Ghevaert, Cédric

doi:10.1182/blood-2014-04-566760

Cited by 78 publications

(107 citation statements)

References 47 publications

(48 reference statements)

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“…This concept is supported by a mouse model in which a steady leak of a-granule contents (ie, cytokines, chemokines, and growth factors) from megakaryocytes into the bone marrow creates a proinflammatory environment that drives the development of fibrosis. 18 In this study we detected a missense mutation in a gene that regulates a-granule secretion, TLR4 (TLR4 W746C ). TLR4 is present on platelets and regulates secretion of cytokines and chemokines from platelets on activation.…”

Section: Discussionmentioning

confidence: 99%

Megakaryocytes in Myeloproliferative Neoplasms Have Unique Somatic Mutations

Guo

Allcock

Mirzai

et al. 2017

The American Journal of Pathology

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Section: Discussionmentioning

confidence: 99%

Megakaryocytes in Myeloproliferative Neoplasms Have Unique Somatic Mutations

Guo

Allcock

Mirzai

et al. 2017

The American Journal of Pathology

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“…1). Studies on various Nbeal2 knockout mouse models confirm that a-granules fail to form in MKs and/or be translocated into proplatelets and newly formed platelets [15][16][17]. These mouse models of GPS highlight how platelet a-granule proteins intervene in tissue repair, cause an inflammatory state in the marrow and contribute to thromboinflammatory states in the circulation (e.g., cerebral ischemia) and facilitate cancer metastasis thereby further raising interest in the disease.…”

Section: Gray Platelet Syndrome and The Nbeal2 Genementioning

confidence: 95%

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Nurden

2016

American J Hematol

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There is much current interest in the role of the platelet storage pool of α‐granule proteins both in hemostasis and non‐hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of α‐granules and their contents. While NBEAL2 is the major source of mutations in GPS, other gene variants may give rise to significant α‐granule deficiencies in platelets. These include GATA1, VPS33B, or VIPAS39 in the arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and now GFI1B. Nevertheless, many phenotypic differences are associated with mutations in these genes. This critical review was aimed to assess genotype/phenotype variability in disorders of platelet α‐granule biogenesis and to urge caution in grouping all genetic defects of α‐granules as GPS. Am. J. Hematol. 91:714–718, 2016. © 2016 Wiley Periodicals, Inc.

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“…Three mouse models with knockout of Nbeal2 have been generated recently. [104][105][106][107] While all three reproduce the macrothrombocytopenia and lack of α-granules in platelets, they display differences which are worth noting. The study from Kahr et al, 107 (Model 1), reports splenomegaly, like the human pathology, but no myelofibrosis.…”

Section: Gray Platelet Syndromementioning

confidence: 99%

“…Since proplatelet formation and platelet survival are normal, the authors propose that the thrombocytopenia results from defects in the terminal stages of platelet release. Finally, the mouse line developed by Guerrero et al, 106 (Model 3), displays both splenomegaly and myelofibrosis. In situ, the megakaryocytes are smaller and generally less polylobed, while ultrastructural images reveal a slightly more rudimentary DMS.…”

Section: Gray Platelet Syndromementioning

confidence: 99%

The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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Article summary• Constitutional thrombocytopenias of hereditary origin have long been poorly studied due to the difficulties of obtaining invasive marrow samples.• Genetic engineering has allowed the generation of numerous mouse models for all these pathologies, providing invaluable information to understanding these diseases and serving as preclinical models to test new therapies.Constitutional thrombocytopenias result from genetic mutations affecting platelet production. These rare diseases are still underdiagnosed, especially in adults, because they remain little-known and have a highly variable expression. Autoimmune thrombocytopenia is still often wrongly diagnosed, thereby leading to the inadequate management of patients, with occasionally inappropriate splenectomy. The diagnosis of congenital thrombocytopenia relies on cytological and functional platelet analyses performed almost exclusively in specialized laboratories. Furthermore, about 50% of thrombocytopenias, associated or not with a thrombopathy, still remain of unknown origin. 1 In cases where platelet studies orient the diagnosis to a known disease, the detection of mutations in the suspected genes can C onstitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.The contribution of mouse models to the understanding of constitutional thrombocytope...

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

Abstract: Key Points Proinflammatory MKs from mice with GPS drive the extension of myelofibrosis, splenomegaly, and emperipolesis. The lack of preformed α-granules in Nbeal2−/− platelets leads to protection against cancer metastasis.

Cited by 78 publications

References 47 publications

Megakaryocytes in Myeloproliferative Neoplasms Have Unique Somatic Mutations

Megakaryocytes in Myeloproliferative Neoplasms Have Unique Somatic Mutations

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

The contribution of mouse models to the understanding of constitutional thrombocytopenia

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