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From the same journal

JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms

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Published copy (DOI)

Author(s)

  • S Leah Etheridge
  • Michelle E Roh
  • Megan E Cosgrove
  • Veena Sangkhae
  • Norma E Fox
  • Junmei Chen
  • José A López
  • Kenneth Kaushansky
  • Ian S Hitchcock

Department/unit(s)

Publication details

JournalProceedings of the National Academy of Sciences of the United States of America
DatePublished - 11 Feb 2014
Issue number6
Volume111
Number of pages6
Pages (from-to)2295-300
Original languageEnglish

Abstract

The Janus kinase 2 (JAK2) V617F mutation is the primary pathogenic mutation in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombohemorrhagic incidents are the most common causes of morbidity and mortality in patients with MPNs, the events causing these clotting abnormalities remain unclear. To identify the cells responsible for the dysfunctional hemostasis, we used transgenic mice expressing JAK2V617F in specific lineages involved in thrombosis and hemostasis. When JAK2V617F was expressed in both hematopoietic and endothelial cells (ECs), the mice developed a significant MPN, characterized by thrombocytosis, neutrophilia, and splenomegaly. However, despite having significantly higher platelet counts than controls, these mice showed severely attenuated thrombosis following injury. Interestingly, platelet activation and aggregation in response to agonists was unaltered by JAK2V617F expression. Subsequent bone marrow transplants revealed the contribution of both endothelial and hematopoietic compartments to the attenuated thrombosis. Furthermore, we identified a potential mechanism for this phenotype through JAK2V617F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V617F(+) mice display a condition similar to acquired von Willebrand syndrome, exhibiting significantly less high molecular weight VWF and reduced agglutination to ristocetin. These findings greatly advance our understanding of thrombohemorrhagic events in MPNs and highlight the critical role of ECs in the pathology of hematopoietic malignancies.

    Research areas

  • Animals, Blood Coagulation Disorders, Blood Platelets, Endothelium, Vascular, Janus Kinase 2, Mice, Mice, Transgenic, Myeloproliferative Disorders, Receptor, TIE-2, von Willebrand Diseases

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