Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis.
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.
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Do-Kyun
DK
Kim
Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Michael A
MA
Beaven
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Joseph M
JM
Kulinski
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Avanti
A
Desai
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Geethani
G
Bandara
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Yun
Y
Bai
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Calman
C
Prussin
Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Lawrence B
LB
Schwartz
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Hirsh
H
Komarow
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Dean D
DD
Metcalfe
Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Ana
A
Olivera
D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D005110:Extracellular Space / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008407:Mast Cells / Q000378:metabolism; D034801:Mastocytoma / Q000473:pathology; D008415:Mastocytosis / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000071617:Protein Deglycase DJ-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D014158:Transcription, Genetic
D000975:Antioxidants; D017382:Reactive Oxygen Species; D019947:Receptors, Interleukin-6; D019009:Proto-Oncogene Proteins c-kit; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1