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dc.contributor.authorHemsing, Anette Lodvir
dc.contributor.authorRye, Kristin Paulsen
dc.contributor.authorHatfield, Kimberley Joanne
dc.contributor.authorReikvam, Håkon
dc.date.accessioned2022-09-22T12:50:39Z
dc.date.available2022-09-22T12:50:39Z
dc.date.created2022-09-16T12:52:19Z
dc.date.issued2022
dc.identifier.issn2227-9059
dc.identifier.urihttps://hdl.handle.net/11250/3020703
dc.description.abstractThe prognosis of acute myeloid leukemia (AML) is poor, especially for the elderly population. Targeted therapy with small molecules may be a potential strategy to overcome chemoresistance and improve survival in AML. We investigated the inhibition of the signaling molecule ras-related C3 botulinum toxin substrate 1 (Rac1) in leukemia cells derived from 79 consecutive AML patients, using five Rac1 inhibitors: ZINC69391, ITX3, EHOP-016, 1A-116, and NSC23766. In vitro cell proliferation and apoptosis assays and the assessment of cytokine profiles in culture media were conducted. All five inhibitors had an antiproliferative effect; IC50 ranged from 3–24 µM. They induced significant apoptosis and necrosis compared to the untreated controls (p < 0.0001) at concentrations around IC40 and IC80. A high versus an intermediate or low antiproliferative effect was more common in NPM1-mutated (p = 0.002) and CD34-negative (p = 0.008) samples, and when NPM1 and FLT3 (p = 0.027) were combined. Presence of NPM1 mutation was associated with reduced viability after treatment with EHOP-016 (p = 0.014), ITX3 (p = 0.047), and NSC23766 (p = 0.003). Several cytokines crucial for leukemogenesis were reduced after culture, with the strongest effects observed for 1A-116 and NSC23766. Our findings suggest potent effects of Rac1 inhibition in primary AML cells and, interestingly, samples harboring NPM1 mutation seem more vulnerable.en_US
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleNPM1-Mutated Patient-Derived AML Cells Are More Vulnerable to Rac1 Inhibitionen_US
dc.typeJournal articleen_US
dc.typePeer revieweden_US
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2022 by the authorsen_US
dc.source.articlenumber1881en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1
dc.identifier.doi10.3390/biomedicines10081881
dc.identifier.cristin2052472
dc.source.journalBiomedicinesen_US
dc.identifier.citationBiomedicines. 2022, 10 (8), 1881.en_US
dc.source.volume10en_US
dc.source.issue8en_US


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Navngivelse 4.0 Internasjonal
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