Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

• Published in: PloS one Vol. 11; no. 9; p. e0162831
• Main Authors: Kim, Do-Kyun, Beaven, Michael A, Kulinski, Joseph M, Desai, Avanti, Bandara, Geethani, Bai, Yun, Prussin, Calman, Schwartz, Lawrence B, Komarow, Hirsh, Metcalfe, Dean D, Olivera, Ana
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.09.2016; Public Library of Science (PLoS)
• Subjects: Adoptive Transfer; Adult; Allergies; Animals; Antioxidants; Antioxidants (Nutrients); Antioxidants - metabolism; Biology; Biology and Life Sciences; Blocking antibodies; Cancer; Cell Line; Damage; Development and progression; Extracellular Space - metabolism; Gene expression; Genetic aspects; Health aspects; Homeostasis; Humans; Immunology; Infectious diseases; Interleukin 6; Interleukin 6 receptors; Kinases; Laboratories; Mast cells; Mast Cells - metabolism; Mastocytoma - pathology; Mastocytosis; Mastocytosis - blood; Mastocytosis - metabolism; Medical prognosis; Medicine and Health Sciences; Mice; Middle Aged; Mutation; Mutation - genetics; Myeloproliferative diseases; Oxidation; Oxidative stress; Oxidizing agents; Oxygen; PARK7 protein; Parkinson's disease; Patients; Physical Sciences; Protein Deglycase DJ-1 - blood; Protein Deglycase DJ-1 - genetics; Protein Deglycase DJ-1 - metabolism; Protein-tyrosine kinase receptors; Proteins; Proteolysis; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Reactive oxygen species; Reactive Oxygen Species - blood; Reactive Oxygen Species - metabolism; Receptors, Interleukin-6 - metabolism; Research and Analysis Methods; Transcription; Transcription, Genetic; Tyrosine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0162831

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage.