Constitutively activated KIT in mastocytosis patients is associated with decreased levels of the scavenger protein DJ1 and concomitant increases in reactive oxygen species

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIAID	IMMUNO-7

* FARE Award Winner

Authors

• D.K Kim
• M.A Beaven
• G Cruse
• C Prussin
• H Komarov
• M Carter
• D.D Metcalfe
• A Olivera

Abstract

Mastocytosis is characterized by accumulation of mast cells (MC) in various organs. Mastocytosis is linked to clonal gain-of-function mutations in the stem cell factor (SCF) receptor KIT, which is critical for MC proliferation and function. As in other cancers, serum levels of reactive oxygen species (ROS), an indicator of oxidative stress, were elevated in systemic mastocytosis (SM) patients but less so in patients with more aggressive disease. DJ-1, a scavenger of ROS and regulator of MC function, was diminished in SM patients with low to medium tryptase and IL-6 levels, but normal in patients with more severe SM (high tryptase and IL-6 levels). MC lines carrying the same gain-of-function KIT mutations or normal MCs exposed long-term to SCF showed reduced DJ1 expression to indicate a possible consequence of chronic KIT activation. This reduction of DJ1 was reversed by IL-6, which may explain the normal DJ1 levels in more severe SM with high IL-6 levels. We conclude that KIT hyperactivity causes DJ-1 dysregulation and ROS increases in SM, while high IL-6 in severe SM normalizes DJ1 levels. The findings raise the possibility that DJ1 and ROS contribute to SM symptoms and/or progression and may serve as markers of disease progression

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