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

Show simple item record

dc.contributor.author Moloney, Jennifer N.
dc.contributor.author Stanicka, Joanna
dc.contributor.author Cotter, Thomas G.
dc.date.accessioned 2017-07-31T12:12:08Z
dc.date.available 2017-07-31T12:12:08Z
dc.date.issued 2017-11-11
dc.identifier.citation Moloney, 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.2016.11.006 en
dc.identifier.volume 52 en
dc.identifier.startpage 34 en
dc.identifier.endpage 42 en
dc.identifier.issn 0145-2126
dc.identifier.uri http://hdl.handle.net/10468/4412
dc.identifier.doi 10.1016/j.leukres.2016.11.006
dc.description.abstract Internal 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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier 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.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Acute myeloid leukemia en
dc.subject FLT3-ITD en
dc.subject Oncogene en
dc.subject NADPH oxidase en
dc.subject p22 en
dc.subject Pro-survival reactive oxygen species en
dc.title 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 en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Thomas Cotter, School Of Biochemistry & Cell Biology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: t.cotter@ucc.ie en
dc.internal.availability Full text available en
dc.check.info Access to this article is restricted until 12 months after publication by request of the publisher. en
dc.check.date 2017-11-11
dc.date.updated 2017-07-31T11:57:58Z
dc.description.version Accepted Version en
dc.internal.rssid 405049677
dc.contributor.funder Children’s Leukaemia Research Project Ireland
dc.description.status Peer reviewed en
dc.identifier.journaltitle Leukemia Research en
dc.internal.copyrightchecked Yes en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress t.cotter@ucc.ie en


Files in this item

This item appears in the following Collection(s)

Show simple item record

© 2016 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license. Except where otherwise noted, this item's license is described as © 2016 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.
This website uses cookies. By using this website, you consent to the use of cookies in accordance with the UCC Privacy and Cookies Statement. For more information about cookies and how you can disable them, visit our Privacy and Cookies statement