Subcellular localization of the FLT3-ITD oncogene plays a significant role in the production of NOX- and p22phox-derived reactive oxygen species in acute myeloid leukemia

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dc.contributor.authorMoloney, Jennifer N.
dc.contributor.authorStanicka, Joanna
dc.contributor.authorCotter, Thomas G.
dc.contributor.funderChildren’s Leukaemia Research Project Ireland
dc.date.accessioned2017-07-31T12:12:08Z
dc.date.available2017-07-31T12:12:08Z
dc.date.issued2017-11-11
dc.date.updated2017-07-31T11:57:58Z
dc.description.abstractInternal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) receptor is the most prevalent FLT3 mutation accounting for 20% of acute myeloid leukemia (AML) patients. FLT3-ITD mutation results in ligand-independent constitutive activation of the receptor at the plasma membrane and ‘impaired trafficking’ of the receptor in compartments of the endomembrane system, such as the endoplasmic reticulum (ER). FLT3-ITD expressing cells have been shown to generate increased levels of reactive oxygen species (ROS), in particular NADPH oxidase (NOX)-generated ROS which act as pro-survival signals. The purpose of this study is to investigate FLT3-ITD production of ROS at the plasma membrane and ER in the FLT3-ITD expressing AML cell line MV4-11. Receptor trafficking inhibitors; Tunicamycin and Brefeldin A induce ER retention of FLT3-ITD, resulting in a decrease in protein expression of NOX4 and its partner protein p22phox, thus demonstrating the critical importance of FLT3-ITD localization for the generation of pro-survival ROS. NOX-generated ROS contribute to total endogenous hydrogen peroxide (H2O2) in AML as quantified by flow cytometry using the cell-permeable H2O2-probe Peroxy Orange 1 (PO1). We found that PI3K/AKT signaling only occurs when FLT3-ITD is expressed at the plasma membrane and is required for the production of NOX-generated ROS. ER retention of FLT3-ITD resulted in NOX4 deglycosylation and p22phox protein degradation.en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMoloney, J. N., Stanicka, J. and Cotter, T. G. (2016) 'Subcellular localization of the FLT3-ITD oncogene plays a significant role in the production of NOX- and p22phox-derived reactive oxygen species in acute myeloid leukemia', Leukemia Research, 52, pp. 34-42. doi:10.1016/j.leukres.2016.11.006en
dc.identifier.doi10.1016/j.leukres.2016.11.006
dc.identifier.endpage42en
dc.identifier.issn0145-2126
dc.identifier.journaltitleLeukemia Researchen
dc.identifier.startpage34en
dc.identifier.urihttps://hdl.handle.net/10468/4412
dc.identifier.volume52en
dc.language.isoenen
dc.publisherElsevier Ltd.en
dc.rights© 2016 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectAcute myeloid leukemiaen
dc.subjectFLT3-ITDen
dc.subjectOncogeneen
dc.subjectNADPH oxidaseen
dc.subjectp22en
dc.subjectPro-survival reactive oxygen speciesen
dc.titleSubcellular localization of the FLT3-ITD oncogene plays a significant role in the production of NOX- and p22phox-derived reactive oxygen species in acute myeloid leukemiaen
dc.typeArticle (peer-reviewed)en
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