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PXD032104

PXD032104 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleBlockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies
DescriptionMutations in the type III receptor tyrosine kinase FLT3 are frequent in patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is characterized by the overproduction of reactive oxygen species (ROS), which can induce cysteine oxidation in redox-sensitive signaling proteins. Here, we sought to characterize the specific pathways affected by ROS in AML by assessing oncogenic signaling in primary AML samples. The oxidation or phosphorylation of signaling proteins that mediate growth and proliferation was increased in samples from patient subtypes with FLT3 mutations. These samples also showed increases in the oxidation of proteins in the ROS-producing Rac/NADPH oxidase-2 (NOX2) complex. Inhibition of NOX2 increased the apoptosis of FLT3-mutant AML cells in response to FLT3 inhibitors. NOX2 inhibition also reduced the phosphorylation and cysteine oxidation of FLT3 in patient-derived xenograft mouse models, suggesting that decreased oxidative stress reduces the oncogenic signaling of FLT3. In mice grafted with FLT3 mutant AML cells, treatment with a NOX2 inhibitor reduced the number of circulating cancer cells, and combining FLT3 and NOX2 inhibitors increased survival to a greater extent than either treatment alone. Together, these data raise the possibility that combining NOX2 and FLT3 inhibitors could improve the treatment of FLT3 mutant AML.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_08:45:28.480.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterZac Germon
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListN-ethylmaleimide derivatized cysteine; phosphorylated residue; iTRAQ8plex-116 reporter+balance reagent acylated residue; monohydroxylated residue
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-03-07 03:52:16ID requested
12023-05-03 00:05:41announced
22023-11-14 08:45:33announced2023-11-14: Updated project metadata.
Publication List
Germon ZP, Sillar JR, Mannan A, Duchatel RJ, Staudt D, Murray HC, Findlay IJ, Jackson ER, McEwen HP, Douglas AM, McLachlan T, Schjenken JE, Skerrett-Byrne DA, Huang H, Melo-Braga MN, Plank MW, Alvaro F, Chamberlain J, De Iuliis G, Aitken RJ, Nixon B, Wei AH, Enjeti AK, Huang Y, Lock RB, Larsen MR, Lee H, Vaghjiani V, Cain JE, de Bock CE, Verrills NM, Dun MD, Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies. Sci Signal, 16(778):eabp9586(2023) [pubmed]
Keyword List
submitter keyword: Redox, PDX, iTRAQ,Leukaemia, AML
Contact List
Matthew Dun
contact affiliationUniversity of Newcastle, Callaghan, NSW, Australia
contact emailmatt.dun@newcastle.edu.au
lab head
Zac Germon
contact affiliationUniversity of Newcastle
contact emailzacary.germon@uon.edu.au
dataset submitter
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Dataset FTP location
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PRIDE project URI
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