Megakaryocytic hyperplasia in myeloproliferative neoplasms is driven by disordered proliferative, apoptotic and epigenetic mechanisms

Jacques Malherbe, Kathryn Fuller, Ayesha Arshad, Jyoti Nangalia, Giuliana Romeo, Sara Hall, Katie Meehan, Belinda Guo, Rebecca Howman, Wendy Erber

    Research output: Contribution to journalArticle

    7 Citations (Scopus)

    Abstract

    Aims: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal proliferative bone marrow diseases characterised by extensive megakaryocytic hyperplasia and morphological atypia. Despite knowledge of genomic defects, the pathobiological processes driving these megakaryocytic abnormalities in MPN remain poorly explained. We have explored the proliferative, apoptotic and epigenetic profiles of megakaryocytes in human MPN.

    Methods: Immunohistochemical staining was performed on bone marrow trephine biopsies of 81 MPN (with and without JAK2V617F and CALR mutations) and 15 normal controls to assess the megakaryocytic expression of biomarkers associated with proliferation (Ki67), apoptosis (Bcl-XL, BNIP-3) and epigenetic regulation (EZH2, SUZ12).

    Results: Myeloproliferative megakaryocytes showed significantly greater expression of proliferative Ki67 and anti-apoptotic Bcl-XL, reduced pro-apoptotic BNIP-3 and increased SUZ12 compared with controls. In essential thrombocythaemia, large-giant megakaryocytes with hyperlobated nuclei showed a trend towards a proliferative signature. In contrast, myelofibrotic megakaryocytes with condensed nuclear chromatin, and cases with CALR mutations, had significant reductions in pro-apoptotic BNIP-3.

    Conclusions: Uncontrolled megakaryocytic expansion in MPN results from a combination of increased proliferation, attenuated apoptosis and defective epigenetic regulation with CALR mutations favouring apoptotic failure. The higher platelet counts reported to be seen in MPN with CALR mutations may be due to greater dysregulation of megakaryocyte apoptosis.
    Original languageEnglish
    Pages (from-to)155-163
    JournalJournal of Clinical Pathology
    Volume69
    Issue number2
    DOIs
    Publication statusPublished - 2016

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    Megakaryocytes
    Epigenomics
    Hyperplasia
    Neoplasms
    Mutation
    Apoptosis
    Bone Marrow Diseases
    Essential Thrombocythemia
    Platelet Count
    Chromatin
    Biomarkers
    Bone Marrow
    Staining and Labeling
    Biopsy

    Cite this

    @article{96edbcf7c652448982702424473c53fe,
    title = "Megakaryocytic hyperplasia in myeloproliferative neoplasms is driven by disordered proliferative, apoptotic and epigenetic mechanisms",
    abstract = "Aims: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal proliferative bone marrow diseases characterised by extensive megakaryocytic hyperplasia and morphological atypia. Despite knowledge of genomic defects, the pathobiological processes driving these megakaryocytic abnormalities in MPN remain poorly explained. We have explored the proliferative, apoptotic and epigenetic profiles of megakaryocytes in human MPN.Methods: Immunohistochemical staining was performed on bone marrow trephine biopsies of 81 MPN (with and without JAK2V617F and CALR mutations) and 15 normal controls to assess the megakaryocytic expression of biomarkers associated with proliferation (Ki67), apoptosis (Bcl-XL, BNIP-3) and epigenetic regulation (EZH2, SUZ12).Results: Myeloproliferative megakaryocytes showed significantly greater expression of proliferative Ki67 and anti-apoptotic Bcl-XL, reduced pro-apoptotic BNIP-3 and increased SUZ12 compared with controls. In essential thrombocythaemia, large-giant megakaryocytes with hyperlobated nuclei showed a trend towards a proliferative signature. In contrast, myelofibrotic megakaryocytes with condensed nuclear chromatin, and cases with CALR mutations, had significant reductions in pro-apoptotic BNIP-3.Conclusions: Uncontrolled megakaryocytic expansion in MPN results from a combination of increased proliferation, attenuated apoptosis and defective epigenetic regulation with CALR mutations favouring apoptotic failure. The higher platelet counts reported to be seen in MPN with CALR mutations may be due to greater dysregulation of megakaryocyte apoptosis.",
    author = "Jacques Malherbe and Kathryn Fuller and Ayesha Arshad and Jyoti Nangalia and Giuliana Romeo and Sara Hall and Katie Meehan and Belinda Guo and Rebecca Howman and Wendy Erber",
    year = "2016",
    doi = "10.1136/jclinpath-2015-203177",
    language = "English",
    volume = "69",
    pages = "155--163",
    journal = "Journal of Clinical Pathology",
    issn = "0021-9746",
    publisher = "BMJ Publishing Group",
    number = "2",

    }

    Megakaryocytic hyperplasia in myeloproliferative neoplasms is driven by disordered proliferative, apoptotic and epigenetic mechanisms. / Malherbe, Jacques; Fuller, Kathryn; Arshad, Ayesha; Nangalia, Jyoti; Romeo, Giuliana; Hall, Sara; Meehan, Katie; Guo, Belinda; Howman, Rebecca; Erber, Wendy.

    In: Journal of Clinical Pathology, Vol. 69, No. 2, 2016, p. 155-163.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Megakaryocytic hyperplasia in myeloproliferative neoplasms is driven by disordered proliferative, apoptotic and epigenetic mechanisms

    AU - Malherbe, Jacques

    AU - Fuller, Kathryn

    AU - Arshad, Ayesha

    AU - Nangalia, Jyoti

    AU - Romeo, Giuliana

    AU - Hall, Sara

    AU - Meehan, Katie

    AU - Guo, Belinda

    AU - Howman, Rebecca

    AU - Erber, Wendy

    PY - 2016

    Y1 - 2016

    N2 - Aims: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal proliferative bone marrow diseases characterised by extensive megakaryocytic hyperplasia and morphological atypia. Despite knowledge of genomic defects, the pathobiological processes driving these megakaryocytic abnormalities in MPN remain poorly explained. We have explored the proliferative, apoptotic and epigenetic profiles of megakaryocytes in human MPN.Methods: Immunohistochemical staining was performed on bone marrow trephine biopsies of 81 MPN (with and without JAK2V617F and CALR mutations) and 15 normal controls to assess the megakaryocytic expression of biomarkers associated with proliferation (Ki67), apoptosis (Bcl-XL, BNIP-3) and epigenetic regulation (EZH2, SUZ12).Results: Myeloproliferative megakaryocytes showed significantly greater expression of proliferative Ki67 and anti-apoptotic Bcl-XL, reduced pro-apoptotic BNIP-3 and increased SUZ12 compared with controls. In essential thrombocythaemia, large-giant megakaryocytes with hyperlobated nuclei showed a trend towards a proliferative signature. In contrast, myelofibrotic megakaryocytes with condensed nuclear chromatin, and cases with CALR mutations, had significant reductions in pro-apoptotic BNIP-3.Conclusions: Uncontrolled megakaryocytic expansion in MPN results from a combination of increased proliferation, attenuated apoptosis and defective epigenetic regulation with CALR mutations favouring apoptotic failure. The higher platelet counts reported to be seen in MPN with CALR mutations may be due to greater dysregulation of megakaryocyte apoptosis.

    AB - Aims: Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal proliferative bone marrow diseases characterised by extensive megakaryocytic hyperplasia and morphological atypia. Despite knowledge of genomic defects, the pathobiological processes driving these megakaryocytic abnormalities in MPN remain poorly explained. We have explored the proliferative, apoptotic and epigenetic profiles of megakaryocytes in human MPN.Methods: Immunohistochemical staining was performed on bone marrow trephine biopsies of 81 MPN (with and without JAK2V617F and CALR mutations) and 15 normal controls to assess the megakaryocytic expression of biomarkers associated with proliferation (Ki67), apoptosis (Bcl-XL, BNIP-3) and epigenetic regulation (EZH2, SUZ12).Results: Myeloproliferative megakaryocytes showed significantly greater expression of proliferative Ki67 and anti-apoptotic Bcl-XL, reduced pro-apoptotic BNIP-3 and increased SUZ12 compared with controls. In essential thrombocythaemia, large-giant megakaryocytes with hyperlobated nuclei showed a trend towards a proliferative signature. In contrast, myelofibrotic megakaryocytes with condensed nuclear chromatin, and cases with CALR mutations, had significant reductions in pro-apoptotic BNIP-3.Conclusions: Uncontrolled megakaryocytic expansion in MPN results from a combination of increased proliferation, attenuated apoptosis and defective epigenetic regulation with CALR mutations favouring apoptotic failure. The higher platelet counts reported to be seen in MPN with CALR mutations may be due to greater dysregulation of megakaryocyte apoptosis.

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    U2 - 10.1136/jclinpath-2015-203177

    DO - 10.1136/jclinpath-2015-203177

    M3 - Article

    VL - 69

    SP - 155

    EP - 163

    JO - Journal of Clinical Pathology

    JF - Journal of Clinical Pathology

    SN - 0021-9746

    IS - 2

    ER -