The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

Abstract

BackgroundThe JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. Design and MethodsWe evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63 + basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. ResultsWe found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63 + basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63 + basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. ConclusionsThese data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells' abnormal function and, putatively, in the pathogenesis of pruritus.Key words: JAK2V617F mutation, basophil, polycythemia vera, pruritus.Citation: Pieri L, Bogani C, Guglielmelli P, Zingariello M, Rana RA, Bartalucci N, Bosi A, and Vannucchi AM. The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera. Haematologica 2009; 94:1537-1545. doi:10.3324/haematol.2009 This is an open-access paper.The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

Blood cell activation in myeloproliferative neoplasms

“…Until now, the origin of aquagenic pruritus in PV was poorly understood. In this context, the findings by Pieri et al 26 support a pathogenic role for basophil activation in the appearance of this symptom. Since the status of the mast cells in JAK2 -positive myeloproliferative neoplasms is not well known, their possible activation could be an alternative explanation for the genesis of the pruritus.…”

“…Both types of cells have granules that contain histamine, platelet-activating factor, and bioactive proteoglycans, and their degranulation is mediated by the Fc-epsilon receptor, generally triggered by aggregated IgE. In this issue of the journal, Pieri et al 26 report the results of the first study aimed at investigating the function of basophils in myeloproliferative neoplasms according to the patients' JAK2 mutational status, showing an increased number of activated basophils in PV patients, both at baseline and after stimulation. The fact that the percentage of circulating activated basophils was correlated with the presence of aquagenic pruritus and with the JAK2 allelic burden would indicate that basophil activation is driven by the JAK2 mutation, and, probably mediates aquagenic pruritus.…”

“…The degree of activation is correlated with the mutated allelic burden and would be either responsible for or a contributor to some of the most characteristic clinical manifestations of the myeloproliferative neoplasms, such as aquagenic pruritus and thrombosis. In addition to casting light onto the pathogenesis of the myeloproliferative neoplasms, the results of the study by Pieri et al 26 provide a further rationale for the use of JAK2 inhibitors in these diseases.…”

Aquagenic pruritus in polycythemia vera: Characteristics and influence on quality of life in 441 patients

“…We have shown that the JAK2 mutation is present in mast cells of the skin of patients with PV (F.P.S., J.T., Karl Sotlar, P.E.P., manuscript in preparation), others have demonstrated that the JAK2V617F mutation occurs in basophils of patients with PV [25]. If long-term studies demonstrate a good tolerability, JAK2 inhibitors may also play a role in the treatment of AP in PV as shown for myelofibrosis patients.…”

Management of symptoms in polycythemia vera and essential thrombocythemia patients

“…Progression to acute myeloid leukemia (AML) is almost uniformly fatal within 12 months of diagnosis and observed in up to 8% of the MPN population. 10 The prevalence of PV (44-57 per 100 000 persons) and ET (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57) per 100 000 persons) is much higher than for MF in the United States. 11 These patients have a longer median survival of 14 and 20 years, respectively, compared to 6-8 years for patients with MF.…”