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Chronic myeloproliferative neoplasms

JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation

Leukemia volume 30, pages 2332–2341 (2016)Cite this article

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Abstract

The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs, but the mechanism(s) responsible for MPN stem cell expansion remain incomplete. One hallmark feature of the marrow in patients with MPNs is megakaryocyte (MK) hyperplasia. We report here that mice bearing a human JAK2V617F gene restricted exclusively to the MK lineage develop many of the features of a MPN. Specifically, these mice exhibit thrombocytosis, splenomegaly, increased numbers of marrow and splenic hematopoietic progenitors and a substantial expansion of HSPCs. In addition, wild-type mice transplanted with cells from JAK2V617F-bearing MK marrow develop a myeloproliferative syndrome with thrombocytosis and erythrocytosis as well as pan-hematopoietic progenitor and stem cell expansion. As marrow histology in this murine model of myeloproliferation reveals a preferentially perivascular localization of JAK2V617F-mutant MKs and an increased marrow sinusoid vascular density, it adds to accumulating data that MKs are an important component of the marrow HSPC niche, and that MK expansion might indirectly contribute to the critical role of the thrombopoietin/c-Mpl signaling pathway in HSPC maintenance and expansion.

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Acknowledgements

The authors thank Dr Ian Hitchcock (University of York, UK) for his scientific consultation and Ms. Laurie Levine (Stony Brook University, NY, USA) for her assistance with the animal work. We thank Dr Radek Skoda (University Hospital Basal, Switzerland) for furnishing the mice (FF1 and Pf4-Cre) and for many fruitful discussions. We thank Drs Stanley Zucker and Hussein Foda(Northport VA Medical Center) for their continuing support throughout this work. This research was supported by the Veterans Affairs Career Development Award CDA210959632 (HZ) and National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK049855 (KK).

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Northport VA Medical Center, Northport, NY, USA

    H Zhan

  2. Department of Medicine, Division of Hematology-Oncology, Stony Brook University, Stony Brook, NY, USA

    H Zhan & C H S Lin

  3. Department of Pathology, Stony Brook University, Stony Brook, NY, USA

    Y Ma

  4. Office of the Sr Vice President, Health Sciences, Stony Brook Medicine, NY, USA

    K Kaushansky

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Zhan, H., Ma, Y., Lin, C. et al. JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation. Leukemia 30, 2332–2341 (2016). https://doi.org/10.1038/leu.2016.114

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