Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production
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|Title:||Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production
|Author:||Tobío Ageitos, Araceli
Morris, Denise A.
O'Connell, Michael P.
Komarow, Hirsh D.
Carter, Melody C.
Metcalfe, Dean D.
|Affiliation:||Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
|Subject:||Chronic Myeloproliferative Disorders | D816V-KIT | IL-6 | STAT5 | Systemic mastocytosis ||
|Date of Issue:||2019-04-02
|Publisher:||Ferrata Storti Foundation
|Citation:||Araceli Tobío, Geethani Bandara, Denise A. Morris, Do-Kyun Kim, Michael P. O'Connell, Hirsh D. Komarow, Melody C. Carter, Daniel Smrz, Dean D. Metcalfe, and Ana Olivera. Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production. Haematologica. 2019; 104:xxx doi:10.3324/haematol.2018.212126
|Abstract:||Persistent dysregulation of IL-6 production and signaling have been implicated in the pathology of various cancers. In systemic mastocytosis, increased serum levels of IL-6 associate with disease severity and progression, although the mechanisms involved are not well understood. Since systemic mastocytosis often associates with the presence in hematopoietic cells of a somatic gain-of-function variant in KIT, D816V-KIT, we examined its potential role in IL-6 upregulation. Bone marrow mononuclear cultures from patients with greater D816V allelic burden released increased amounts of IL-6 which correlated with the percentage of mast cells in the cultures. Intracellular IL-6 staining by flow cytometry and immunofluorescence was primarily associated with mast cells and suggested a higher percentage of IL-6 positive mast cells in patients with higher D816V allelic burden. Furthermore, mast cell lines expressing D816V-KIT, but not those expressing normal KIT or other KIT variants, produced constitutively high IL-6 amounts at the message and protein levels. We further demonstrate that aberrant KIT activity and signaling are critical for the induction of IL-6 and involve STAT5 and PI3K pathways but not STAT3 or STAT4. Activation of STAT5A and STATB downstream of D816V-KIT was mediated by JAK2 but also by MEK/ERK1/2, which not only promoted STAT5 phosphorylation but also its long-term transcription. Our study thus supports a role for mast cells and D816V-KIT activity in IL-6 dysregulation in mastocytosis and provides insights into the intracellular mechanisms. The findings contribute to a better understanding of the physiopathology of mastocytosis and suggest the importance of therapeutic targeting of these pathways|
|Rights:||Copyright © 2019, Ferrata Storti Foundation
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