Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies.

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.

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

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Publisher:: American Association for the Advancement of Science (AAAS)
Publication Type:: Journal Article
Citation:: Sci Signal, 2023, 16, (778), pp. eabp9586
Issue Date:: 2023-03-28

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Field	Value	Language
dc.contributor.author	Germon, ZP
dc.contributor.author	Sillar, JR
dc.contributor.author	Mannan, A
dc.contributor.author	Duchatel, RJ
dc.contributor.author	Staudt, D
dc.contributor.author	Murray, HC
dc.contributor.author	Findlay, IJ
dc.contributor.author	Jackson, ER
dc.contributor.author	McEwen, HP
dc.contributor.author	Douglas, AM
dc.contributor.author	McLachlan, T
dc.contributor.author	Schjenken, JE
dc.contributor.author	Skerrett-Byrne, DA
dc.contributor.author	Huang, H
dc.contributor.author	Melo-Braga, MN
dc.contributor.author	Plank, MW
dc.contributor.author	Alvaro, F
dc.contributor.author	Chamberlain, J
dc.contributor.author	De Iuliis, G
dc.contributor.author	Aitken, RJ
dc.contributor.author	Nixon, B
dc.contributor.author	Wei, AH
dc.contributor.author	Enjeti, AK
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110
dc.contributor.author	Lock, RB
dc.contributor.author	Larsen, MR
dc.contributor.author	Lee, H
dc.contributor.author	Vaghjiani, V
dc.contributor.author	Cain, JE
dc.contributor.author	de Bock, CE
dc.contributor.author	Verrills, NM
dc.contributor.author	Dun, MD
dc.date.accessioned	2024-04-30T03:41:46Z
dc.date.available	2024-04-30T03:41:46Z
dc.date.issued	2023-03-28
dc.identifier.citation	Sci Signal, 2023, 16, (778), pp. eabp9586
dc.identifier.issn	1945-0877
dc.identifier.issn	1937-9145
dc.identifier.uri	http://hdl.handle.net/10453/178493
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for the Advancement of Science (AAAS)
dc.relation.ispartof	Sci Signal
dc.relation.isbasedon	10.1126/scisignal.abp9586
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0601 Biochemistry and Cell Biology
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Cysteine
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Mutation
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	fms-Like Tyrosine Kinase 3
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Cysteine
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Mutation
dc.subject.mesh	fms-Like Tyrosine Kinase 3
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Cysteine
dc.subject.mesh	Leukemia, Myeloid, Acute
dc.subject.mesh	Mutation
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	fms-Like Tyrosine Kinase 3
dc.title	Blockade of ROS production inhibits oncogenic signaling in acute myeloid leukemia and amplifies response to precision therapies.
dc.type	Journal Article
utslib.citation.volume	16
utslib.location.activity	United States
utslib.for	0601 Biochemistry and Cell Biology
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	closed_access	*
dc.date.updated	2024-04-30T03:41:43Z
pubs.issue	778
pubs.publication-status	Published
pubs.volume	16
utslib.citation.issue	778

Abstract:

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.

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http://hdl.handle.net/10453/178493