The D816V-KIT mutation causes IL-6 upregulation in human mast cells

Authors

• A Tobío
• P Hanjra
• G Bandara
• HD Komarow
• MC Carter
• D Cantave
• DD Metcalfe
• A Olivera

Abstract

Increased IL-6 plasma levels in patients with systemic mastocytosis (SM) have been associated with disease severity and progression. However, the cells mainly responsible for the increased IL-6 production in mastocytosis and the mechanisms involved are not known. We found that in the bone marrow of patients with SM carrying D816V-KIT, but not in D816V-KIT negative patients, mast cells (CD3-/CD34-/KIT+/Fc¿RI+) were the major source of IL-6 by intracellular IL-6 immunofluorescent staining and flow cytometry. Moreover, IL-6 plasma levels in patients with SM positively correlated with the frequency of D816V-KIT mutation measured in peripheral blood. We further demonstrate that mast cells expressing D816V-KIT produce IL-6 at the message and protein levels without an exogenous stimulus, while cells expressing normal KIT or other KIT mutations do not, suggesting an association between this specific KIT mutation and the ability of non-activated mast cells to produce IL-6. In agreement, inhibition of KIT activity blunted the ability of these cells to produce IL-6. In conclusion, mast cells appear to be an important cell source for the increased IL-6 plasma levels in patients with SM and such upregulation appears a consequence of signals derived from the oncogenic activity of D816V-KIT. Our studies provide insight into the signalling of mutated KIT and IL-6 deregulation in SM, and which in turn allows a better understanding of the physiopathology of the mastocytosis and the importance of therapeutic approaches that target this receptor and downstream signalling pathways.

Scientific Focus Area: Cancer Biology

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