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dc.contributor.authorForthun, Rakel Brendsdal
dc.contributor.authorHellesøy, Monica
dc.contributor.authorSulen, Andre
dc.contributor.authorKopperud, Reidun Kristin
dc.contributor.authorSjøholt, Gry
dc.contributor.authorBruserud, Øystein
dc.contributor.authorMcCormack, Emmet
dc.contributor.authorGjertsen, Bjørn Tore
dc.date.accessioned2019-09-19T08:22:39Z
dc.date.available2019-09-19T08:22:39Z
dc.date.created2019-07-03T18:36:54Z
dc.date.issued2019
dc.identifier.citationForthun, R. B., Hellesøy, M., Sulen, A., Kopperud, R. K., Sjøholt, G., Bruserud, Ø., . . . Gjertsen, B. T. (2019). Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia. Journal of Cancer Research and Clinical Oncology, 145, 1729-1749.nb_NO
dc.identifier.issn0171-5216
dc.identifier.urihttp://hdl.handle.net/11250/2617587
dc.description.abstractPurpose Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFNα) in various cancers. Therefore, we examined IFNα and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics. Methods The anti-leukemic effects of IFNα and VPA were examined in vitro and in vivo. We mapped the in vitro phosphoprotein modulation by IFNα-2b and human IFNα-Le in MOLM-13 cells by IMAC/2D DIGE/MS analysis and phospho-flow cytometry, and in primary healthy and AML patient-derived PBMCs by CyTOF. In vivo, IFNα-Le and VPA efficacy were investigated in the immunodeficient NOD/Scid IL2γ−/− MOLM-13Luc+ mouse model and the syngeneic immunocompetent BNML rat model. Results IFNα-2b and IFNα-Le differed in the modulation of phospho-proteins involved in protein folding, cell stress, cell death and p-STAT6 Y641, whereas VPA and IFNα-Le shared signaling pathways involving phosphorylation of Akt (T308), ERK1/2 (T202/T204), p38 (T180/Y182), and p53 (S15). Both IFNα compounds induced apoptosis synergistically with VPA in vitro. However, in vivo, VPA monotherapy increased survival, but no benefit was observed by IFNα-Le treatment. CyTOF analysis of primary human PBMCs indicated that lack of immune-cell activation could be a reason for the absence of response to IFNα in the animal models investigated. Conclusions IFNα-2b and IFNα-Le showed potent and synergistic anti-leukemic effects with VPA in vitro but not in leukemic mouse and rat models in vivo. The absence of IFNα immune activation in lymphocyte subsets may potentially explain the limited in vivo anti-leukemic effect of IFNα-monotherapy in AML.nb_NO
dc.language.isoengnb_NO
dc.publisherSpringernb_NO
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.subjectAMLnb_NO
dc.subjectIFNαnb_NO
dc.subjectVPAnb_NO
dc.subjectPhospho-flownb_NO
dc.subjectCyTOFnb_NO
dc.subjectPhosphoproteomenb_NO
dc.titleModulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemianb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.description.versionpublishedVersionnb_NO
dc.rights.holder© The Author(s) 2019.nb_NO
dc.subject.nsiVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762nb_NO
dc.source.pagenumber1729-1749nb_NO
dc.source.volume145nb_NO
dc.source.journalJournal of Cancer Research and Clinical Oncologynb_NO
dc.source.issue7nb_NO
dc.identifier.doi10.1007/s00432-019-02931-1
dc.identifier.cristin1709934
dc.relation.projectHelse Vest: HV 912160nb_NO
dc.relation.projectSolveig & Ole Lunds Legacy: 104712, 145268, 145269, 163424nb_NO
cristin.unitcode203,12,1,0
cristin.unitnameInstitutt for bio- og kjemiingeniørfag
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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