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

Simple item page
dc.contributor.authorMoloney, Jennifer N.
dc.contributor.authorJayavelu, Ashok Kumar
dc.contributor.authorStanicka, Joanna
dc.contributor.authorRoche, Sarah L.
dc.contributor.authorO'Brien, Rebecca L.
dc.contributor.authorScholl, Sebastian
dc.contributor.authorBöhmer, Frank D.
dc.contributor.authorCotter, Thomas G.
dc.contributor.funderCHILDREN with CANCER UK
dc.contributor.funderDeutsche Forschungsgemeinschaft
dc.contributor.funderDeutscher Akademischer Austauschdienst
dc.date.accessioned2018-06-15T11:47:14Z
dc.date.available2018-06-15T11:47:14Z
dc.date.issued2017
dc.description.abstractInternal 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.en
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG BO 1043/102); Children with Cancer, UK (Children’s Leukaemia Research Project)en
dc.description.statusPeer reviewed
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMoloney, J. N., Jayavelu, A. K., Stanicka, J., Roche, S. L., O'Brien, R. L., Scholl, S., Böhmer, F.-D. and Cotter, T. G. (2017) 'Nuclear membrane-localised NOX4D generates pro-survival ROS in FLT3-ITD-expressing AML', Oncotarget, 8(62), pp. 105440-105457. doi: 10.18632/oncotarget.22241en
dc.identifier.doi10.18632/oncotarget.22241
dc.identifier.endpage105457
dc.identifier.issn1949-2553
dc.identifier.issued62
dc.identifier.journaltitleOncotargeten
dc.identifier.startpage105440
dc.identifier.urihttps://hdl.handle.net/10468/6339
dc.identifier.volume8
dc.language.isoenen
dc.publisherImpact Journalsen
dc.relation.urihttp://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22241&path[]=70409
dc.rights© 2017, 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.en
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.subjectAcute myeloid leukaemiaen
dc.subjectFLT3-ITDen
dc.subjectPro-survival reactive oxygen speciesen
dc.subjectNOX4 splice variant D/NOX4D 28 kDaen
dc.subjectNuclear membraneen
dc.titleNuclear membrane-localised NOX4D generates pro-survival ROS in FLT3-ITD-expressing AMLen
dc.typeArticle (peer-reviewed)en
Files
Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Nuclear membrane-localised NOX4D generates pro-survival ROS.pdf
Size:
8.07 MB
Format:
Adobe Portable Document Format
Description:
Published Version
Download
Thumbnail Image
Name:
Nuclear membrane-localised NOX4D generates pro-survival ROS -1.pdf
Size:
1.11 MB
Format:
Adobe Portable Document Format
Description:
Supplemental File 1
Download
Collections
Biochemistry and Cell Biology - Journal Articles