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. Ho...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5017616?pdf=render |
| _version_ | 1811209133350715392 |
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| author | Do-Kyun Kim Michael A Beaven Joseph M Kulinski Avanti Desai Geethani Bandara Yun Bai Calman Prussin Lawrence B Schwartz Hirsh Komarow Dean D Metcalfe Ana Olivera |
| author_facet | Do-Kyun Kim Michael A Beaven Joseph M Kulinski Avanti Desai Geethani Bandara Yun Bai Calman Prussin Lawrence B Schwartz Hirsh Komarow Dean D Metcalfe Ana Olivera |
| author_sort | Do-Kyun Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T04:33:16Z |
| format | Article |
| id | doaj.art-3e0167753f844c6f8eb86c65501568f3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T04:33:16Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3e0167753f844c6f8eb86c65501568f32022-12-22T03:47:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01119e016283110.1371/journal.pone.0162831Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis.Do-Kyun KimMichael A BeavenJoseph M KulinskiAvanti DesaiGeethani BandaraYun BaiCalman PrussinLawrence B SchwartzHirsh KomarowDean D MetcalfeAna OliveraNeoplastic 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.http://europepmc.org/articles/PMC5017616?pdf=render |
| spellingShingle | Do-Kyun Kim Michael A Beaven Joseph M Kulinski Avanti Desai Geethani Bandara Yun Bai Calman Prussin Lawrence B Schwartz Hirsh Komarow Dean D Metcalfe Ana Olivera Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. PLoS ONE |
| title | Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. |
| title_full | Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. |
| title_fullStr | Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. |
| title_full_unstemmed | Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. |
| title_short | Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis. |
| title_sort | regulation of reactive oxygen species and the antioxidant protein dj 1 in mastocytosis |
| url | http://europepmc.org/articles/PMC5017616?pdf=render |
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