PXD032104

PXD032104 is an original dataset announced via ProteomeXchange.

Title	Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies
Description	Mutations 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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:45:28.480.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zac Germon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	N-ethylmaleimide derivatized cysteine; phosphorylated residue; iTRAQ8plex-116 reporter+balance reagent acylated residue; monohydroxylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-07 03:52:16	ID requested
1	2023-05-03 00:05:41	announced
⏵ 2	2023-11-14 08:45:33	announced	2023-11-14: Updated project metadata.

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]

submitter keyword: Redox, PDX, iTRAQ,Leukaemia, AML

Matthew Dun
contact affiliation	University of Newcastle, Callaghan, NSW, Australia
contact email	matt.dun@newcastle.edu.au
lab head
Zac Germon
contact affiliation	University of Newcastle
contact email	zacary.germon@uon.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD032104

PRIDE project URI

• PRIDE
  1. PXD032104
     1. Label: PRIDE project
     2. Name: Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies