JAK2V^sub 617^F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms

The Janus kinase 2 (JAK2) V...F 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 the...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2014-02, Vol.111 (6), p.2295
Hauptverfasser: Etheridge, S Leah, Roh, Michelle E, Cosgrove, Megan E, Sangkhae, Veena, Fox, Norma E, Chen, Junmei, López, José A, Kaushansky, Kenneth, Hitchcock, Ian S
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Etheridge, S Leah
Roh, Michelle E
Cosgrove, Megan E
Sangkhae, Veena
Fox, Norma E
Chen, Junmei
López, José A
Kaushansky, Kenneth
Hitchcock, Ian S
description The Janus kinase 2 (JAK2) V...F 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 JAK2V...F in specific lineages involved in thrombosis and hemostasis. When JAK2V...F 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 JAK2V...F 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 JAK2V...F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V...F+ 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. (ProQuest: ... denotes formulae/symbols omitted.)
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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 JAK2V...F in specific lineages involved in thrombosis and hemostasis. When JAK2V...F 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 JAK2V...F 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 JAK2V...F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V...F+ 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. 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source Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry
subjects Chromosomes
Genotype & phenotype
Molecular weight
Mutation
Rodents
Thrombosis
Tumors
title JAK2V^sub 617^F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms
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