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NOX2 inhibition red...
NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease
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- Aydin, Ebru (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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- Hallner, Alexander, 1990 (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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- Grauers Wiktorin, Hanna, 1990 (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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- Staffas, Anna, 1982 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Sahlgrenska Cancer Center,Institute of Biomedicine
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- Hellstrand, Kristoffer, 1956 (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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- Martner, Anna, 1979 (författare)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center
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(creator_code:org_t)
- 2018-10-15
- 2019
- Engelska.
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:9, s. 1534-1543
- Relaterad länk:
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https://www.nature.c...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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) x Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-Kras(G12D)) were treated with N-alpha-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(-/-) x LSL-Kras(G12D) x 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- acute myeloid-leukemia
- DNA-damage
- genomic instability
- hydrogen-peroxide
- nadph oxidases
- nk cells
- ros
- histamine
- melanoma
- metastasis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Oncogene
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