927:
The D816V-KIT Mutation Causes IL-6 Upregulation In Human Mast Cells
Monday, March 5, 2018: 2:30 PM
S230AB (Convention Center)
Araceli Tobío, , , , , , ,
RATIONALE: Increased IL-6 plasma levels have been associated with severity and progression of disease in patients with systemic mastocytosis (SM). However, the mechanisms involved in increased IL-6 production and the cells responsible are not known.

METHODS: IL-6 levels from peripheral blood were measured by ELISA and D816V-KIT frequency by Allele Specific qPCR. FACS was performed to quantify intracellular IL-6 in bone marrow cells from patients with SM. In vitro experiments were performed in cellular models to evaluate the relationship between the D816V-KIT mutation (present in 90-95% of patients with SM) and IL-6 upregulation.

RESULTS: IL-6 plasma levels positively correlated with D816V-KIT mutation frequency in peripheral blood. Moreover, we found that mast cells are a major source of IL-6 among bone marrow cells from patients with SM. Furthermore, we observed that cultured mast cells expressing D816V-KIT produce IL-6 at the message and protein levels under baseline conditions, while cells expressing wild type KIT or other KIT mutations do not, suggesting a relationship between D816V-KIT mutation and the ability of these cells to produce IL-6. In accordance, KIT activity inhibition reduced mast cell capacity to release IL-6.

CONCLUSIONS: Mast cells with the D816V-KIT mutation are an important source of IL-6 and appear to be responsible for the increase in IL-6 levels in patients with SM via signals derived from the oncogenic activity of D816V-KIT. Our studies shed light into D816V-KIT signalling and IL-6 production in SM, and allows a better understanding of SM physiopathology and the importance of therapeutic approaches that target KIT and downstream signalling pathways.