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  Nuclear membrane-localised NOX4D generates pro-survival ROS in FLT3-ITD-expressing AML

Moloney, J. N., Jayavelu, A. K., Stanicka, J., Roche, S. L., O'Brien, R. L., Scholl, S., et al. (2017). Nuclear membrane-localised NOX4D generates pro-survival ROS in FLT3-ITD-expressing AML. Oncotarget, 8(62), 105440-105457. doi:10.18632/oncotarget.22241.

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Moloney et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 Creators:
Moloney, Jennifer N.1, Author
Jayavelu, Ashok Kumar2, Author              
Stanicka, Joanna1, Author
Roche, Sarah L.1, Author
O'Brien, Rebecca L.1, Author
Scholl, Sebastian1, Author
Boehmer, Frank-D.1, Author
Cotter, Thomas G.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: ACUTE MYELOID-LEUKEMIA; NADPH OXIDASE NOX4; DNA-DAMAGE; CELL-TRANSFORMATION; SIGNAL-TRANSDUCTION; FLT3 ITD; SUBCELLULAR-LOCALIZATION; INDUCED APOPTOSIS; CRITICAL MEDIATOR; TARGETING FLT3Oncology; Cell Biology; acute myeloid leukaemia; FLT3-ITD; pro-survival reactive oxygen species; NOX4 splice variant D/NOX4D 28 kDa; nuclear membrane;
 Abstract: Internal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) is the most prevalent genetic aberration present in 20-30% of acute myeloid leukaemia (AML) cases and is associated with a poor prognosis. FLT3-ITD expressing cells express elevated levels of NADPH oxidase 4 (NOX4)generated pro-survival hydrogen peroxide (H2O2) contributing to increased levels of DNA oxidation and double strand breaks. NOX4 is constitutively active and has been found to have various isoforms expressed at multiple locations within a cell. The purpose of this study was to investigate the expression, localisation and regulation of NOX4 28 kDa splice variant, NOX4D. NOX4D has previously been shown to localise to the nucleus and nucleolus in various cell types and is implicated in the generation of reactive oxygen species (ROS) and DNA damage. Here, we demonstrate that FLT3ITD expressing-AML patient samples as well as -cell lines express the NOX4D isoform resulting in elevated H2O2 levels compared to FLT3-WT expressing cells, as quantified by flow cytometry. Cell fractionation indicated that NOX4D is nuclear membrane-localised in FLT3-ITD expressing cells. Treatment of MV4-11 cells with receptor trafficking inhibitors, tunicamycin and brefeldin A, resulted in deglycosylation of NOX4 and NOX4D. Inhibition of the FLT3 receptor revealed that the FLT3-ITD oncogene is responsible for the production of NOX4D-generated H2O2 in AML. We found that inhibition of the PI3K/AKT and STAT5 pathways resulted in down-regulation of NOX4D-generated pro-survival ROS. Taken together these findings indicate that nuclear membrane-localised NOX4D-generated pro-survival H2O2 may be contributing to genetic instability in FLT3-ITD expressing AML.

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Language(s): eng - English
 Dates: 2017-11-01
 Publication Status: Published online
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000419563600057
DOI: 10.18632/oncotarget.22241
 Degree: -

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Title: Oncotarget
Source Genre: Journal
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Publ. Info: Impact Journals
Pages: - Volume / Issue: 8 (62) Sequence Number: - Start / End Page: 105440 - 105457 Identifier: ISSN: 1949-2553
CoNE: https://pure.mpg.de/cone/journals/resource/1949-2553