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IFNγ directly count...
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Ujvari, DorinaKarolinska Institutet
(author)
IFNγ directly counteracts imatinib-induced apoptosis of primary human CD34+ CML stem/progenitor cells potentially through the upregulation of multiple key survival factors
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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Taylor & Francis,2022
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:umu-198918
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-198918URI
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https://doi.org/10.1080/2162402X.2022.2109861DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-187706URI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:150415438URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Funding Agencies|Cancer Research Funds of Radiumhemmet [174283]; Thorsmans stiftelse for preleukemiforskning; Cathrine Everts Research Foundation; Lars Hierta Memorial Foundation; Swedish Research Council [2013-08807]; Karolinska Institute Foundation and Funds; Gunnar Grimfors Gavofond for Hematologisk Forskning; Emil Andersson Fund for Medical Research
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Tyrosine kinase inhibitors (TKIs) have dramatically improved the survival in chronic myeloid leukemia (CML), but residual disease typically persists even after prolonged treatment. Several lines of evidence suggest that TKIs administered to CML patients upregulate interferon γ (IFNγ) production, which may counteract the anti-tumorigenic effects of the therapy. We now show that activated T cell-conditioned medium (TCM) enhanced proliferation and counteracted imatinib-induced apoptosis of CML cells, and addition of a neutralizing anti-IFNγ antibody at least partially inhibited the anti-apoptotic effect. Likewise, recombinant IFNγ also reduced imatinib-induced apoptosis of CML cells. This anti-apoptotic effect of IFNγ was independent of alternative IFNγ signaling pathways, but could be notably diminished by STAT1-knockdown. Furthermore, IFNγ upregulated the expression of several anti-apoptotic proteins, including MCL1, PARP9, and PARP14, both in untreated and imatinib-treated primary human CD34+ CML stem/progenitor cells. Our results suggest that activated T cells in imatinib-treated CML patients can directly rescue CML cells from imatinib-induced apoptosis at least partially through the secretion of IFNγ, which exerts a rapid, STAT1-dependent anti-apoptotic effect potentially through the simultaneous upregulation of several key hematopoietic survival factors. These mechanisms may have a major clinical impact, when targeting residual leukemic stem/progenitor cells in CML.
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Malyukova, AlenaDepartment of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden,Karolinska Inst, Sweden
(author)
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Zovko, AnaDivision of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden,Karolinska Univ Hosp Solna, Sweden; Karolinska Inst, Sweden
(author)
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Yektaei-Karin, ElhamDivision of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden,Karolinska Univ Hosp Solna, Sweden; Karolinska Inst, Sweden
(author)
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Madapura, Harsha S.Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden,Karolinska Inst, Sweden
(author)
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Keszei, MartonKarolinska Institutet
(author)
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Nagy, NoemiKarolinska Institutet
(author)
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Lotfi, KouroshLinköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US(Swepub:liu)koulo97
(author)
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Björn, NiclasLinköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten(Swepub:liu)nikbj02
(author)
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Wallvik, JonasUmeå universitet,Avdelningen för medicin,Umea Univ, Sweden(Swepub:umu)jowa0061
(author)
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Stenke, LeifDivision of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden,Karolinska Univ Hosp Solna, Sweden; Karolinska Inst, Sweden
(author)
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Salamon, DanielKarolinska Institutet
(author)
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Karolinska InstitutetDepartment of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
(creator_code:org_t)
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In:Oncoimmunology: Taylor & Francis11:12162-40112162-402X
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Ujvari, Dorina
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Malyukova, Alena
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Zovko, Ana
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Yektaei-Karin, E ...
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Madapura, Harsha ...
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Keszei, Marton
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Nagy, Noemi
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Lotfi, Kourosh
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Björn, Niclas
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Wallvik, Jonas
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Stenke, Leif
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Salamon, Daniel
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- MEDICAL AND HEALTH SCIENCES
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Oncoimmunology
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Umeå University
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Linköping University
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Karolinska Institutet