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

J.A. Guerrero, C. Bennett, L. Van Der Weyden, H. Mckinney, M. Chin, P. Nurden, Z. Mcintyre, E.L. Cambridge, J. Estabel, H. Wardle-Jones, A.O. Speak, Wendy Erber, A. Rendon, W.H. Ouwehand, C.J.G. Ghevaert

    Research output: Contribution to journalArticle

    43 Citations (Scopus)

    Abstract

    © 2014 by The American Society of Hematology. 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.
    Original languageEnglish
    Pages (from-to)3624-3635
    JournalBlood
    Volume124
    Issue number24
    DOIs
    Publication statusPublished - 2014

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    Gray Platelet Syndrome
    Primary Myelofibrosis
    Megakaryocytes
    Platelets
    Blood Platelets
    Neoplasm Metastasis
    Bone
    Hemostatics
    Proteins
    Bone Marrow
    Hemorrhage
    Phenotype
    Mutation
    Blood
    Neoplasms

    Cite this

    Guerrero, J. A., Bennett, C., Van Der Weyden, L., Mckinney, H., Chin, M., Nurden, P., ... Ghevaert, C. J. G. (2014). Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice. Blood, 124(24), 3624-3635. https://doi.org/10.1182/blood-2014-04-566760
    Guerrero, J.A. ; Bennett, C. ; Van Der Weyden, L. ; Mckinney, H. ; Chin, M. ; Nurden, P. ; Mcintyre, Z. ; Cambridge, E.L. ; Estabel, J. ; Wardle-Jones, H. ; Speak, A.O. ; Erber, Wendy ; Rendon, A. ; Ouwehand, W.H. ; Ghevaert, C.J.G. / Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice. In: Blood. 2014 ; Vol. 124, No. 24. pp. 3624-3635.
    @article{b715c4dcbee945ba8b0aab3bc6a40614,
    title = "Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice",
    abstract = "{\circledC} 2014 by The American Society of Hematology. 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.",
    author = "J.A. Guerrero and C. Bennett and {Van Der Weyden}, L. and H. Mckinney and M. Chin and P. Nurden and Z. Mcintyre and E.L. Cambridge and J. Estabel and H. Wardle-Jones and A.O. Speak and Wendy Erber and A. Rendon and W.H. Ouwehand and C.J.G. Ghevaert",
    year = "2014",
    doi = "10.1182/blood-2014-04-566760",
    language = "English",
    volume = "124",
    pages = "3624--3635",
    journal = "Blood",
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    Guerrero, JA, Bennett, C, Van Der Weyden, L, Mckinney, H, Chin, M, Nurden, P, Mcintyre, Z, Cambridge, EL, Estabel, J, Wardle-Jones, H, Speak, AO, Erber, W, Rendon, A, Ouwehand, WH & Ghevaert, CJG 2014, 'Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice' Blood, vol. 124, no. 24, pp. 3624-3635. https://doi.org/10.1182/blood-2014-04-566760

    Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice. / Guerrero, J.A.; Bennett, C.; Van Der Weyden, L.; Mckinney, H.; Chin, M.; Nurden, P.; Mcintyre, Z.; Cambridge, E.L.; Estabel, J.; Wardle-Jones, H.; Speak, A.O.; Erber, Wendy; Rendon, A.; Ouwehand, W.H.; Ghevaert, C.J.G.

    In: Blood, Vol. 124, No. 24, 2014, p. 3624-3635.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Gray platelet syndrome: Proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice

    AU - Guerrero, J.A.

    AU - Bennett, C.

    AU - Van Der Weyden, L.

    AU - Mckinney, H.

    AU - Chin, M.

    AU - Nurden, P.

    AU - Mcintyre, Z.

    AU - Cambridge, E.L.

    AU - Estabel, J.

    AU - Wardle-Jones, H.

    AU - Speak, A.O.

    AU - Erber, Wendy

    AU - Rendon, A.

    AU - Ouwehand, W.H.

    AU - Ghevaert, C.J.G.

    PY - 2014

    Y1 - 2014

    N2 - © 2014 by The American Society of Hematology. 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.

    AB - © 2014 by The American Society of Hematology. 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.

    U2 - 10.1182/blood-2014-04-566760

    DO - 10.1182/blood-2014-04-566760

    M3 - Article

    VL - 124

    SP - 3624

    EP - 3635

    JO - Blood

    JF - Blood

    SN - 0006-4971

    IS - 24

    ER -