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NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease
Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly def...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372471/ https://www.ncbi.nlm.nih.gov/pubmed/30323311 http://dx.doi.org/10.1038/s41388-018-0528-1 |
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author | Aydin, Ebru Hallner, Alexander Grauers Wiktorin, Hanna Staffas, Anna Hellstrand, Kristoffer Martner, Anna |
author_facet | Aydin, Ebru Hallner, Alexander Grauers Wiktorin, Hanna Staffas, Anna Hellstrand, Kristoffer Martner, Anna |
author_sort | Aydin, Ebru |
collection | PubMed |
description | Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-Kras(G12D) × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-Kras(G12D)) were treated with N(α)-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H(2) receptors. M-Kras(G12D) mice developed myeloid leukemia comprising mature CD11b(+)Gr1(+) myeloid cells that produced NOX2-derived ROS. Treatment of M-Kras(G12D) mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-Kras(G12D) mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2(−/−) × LSL-Kras(G12D) × Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer. |
format | Online Article Text |
id | pubmed-6372471 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63724712019-02-14 NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease Aydin, Ebru Hallner, Alexander Grauers Wiktorin, Hanna Staffas, Anna Hellstrand, Kristoffer Martner, Anna Oncogene Article Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-Kras(G12D) × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-Kras(G12D)) were treated with N(α)-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H(2) receptors. M-Kras(G12D) mice developed myeloid leukemia comprising mature CD11b(+)Gr1(+) myeloid cells that produced NOX2-derived ROS. Treatment of M-Kras(G12D) mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-Kras(G12D) mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2(−/−) × LSL-Kras(G12D) × Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer. Nature Publishing Group UK 2018-10-15 2019 /pmc/articles/PMC6372471/ /pubmed/30323311 http://dx.doi.org/10.1038/s41388-018-0528-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Aydin, Ebru Hallner, Alexander Grauers Wiktorin, Hanna Staffas, Anna Hellstrand, Kristoffer Martner, Anna NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease |
title | NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease |
title_full | NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease |
title_fullStr | NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease |
title_full_unstemmed | NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease |
title_short | NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease |
title_sort | nox2 inhibition reduces oxidative stress and prolongs survival in murine kras-induced myeloproliferative disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372471/ https://www.ncbi.nlm.nih.gov/pubmed/30323311 http://dx.doi.org/10.1038/s41388-018-0528-1 |
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