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NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities.

Abstract

This study exploited alloreactivity of natural killer (NK) cells for augmenting the recognition of human acute myeloid leukemia (AML). To circumvent the inhibitory effect of killer immunoglobulin receptor (KIR) signaling, we generated NK-cell lines with single KIR specificities for major human leukocyte antigen (HLA) class I allotypes. We demonstrated efficient cytolysis of KIR-HLA class I-mismatched primary AML blasts even at low effector-to-target ratios. To define the impact of tumor-associated activating NKG2D-ligands (NKG2D-L), 66 AML patients at diagnosis were analyzed. NKG2D-L were selectively expressed on monoblastic cells in AML M4 and M5 yet absent or weakly expressed on myeloblastic cells in all AML subtypes. Paucity of cell-surface NKG2D-L was not the result of shedding because levels of soluble ULBP1 ligand measured in AML plasma were in the normal range. Notably, purified NKG2D-L(+) monoblastic cells were more susceptible to NK-mediated killing than NKG2D-L(-) myeloblastic cells. Accordingly, induction of cell-surface NKG2D-L by treatment with the histone deacetylase inhibitor, valproic acid, rendered cells more sensitive to NK cytolysis. These data suggest that adoptive transfer of selected populations of alloreactive HLA class I-mismatched NK cells in combination with pharmacologic induction of NKG2D-L merits clinical evaluation as novel approaches to immunotherapy of human AML.

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  • Authors+Show Affiliations

    ,

    Department of Research, University Hospital Basel, Basel, Switzerland.

    , , , , , , , , , , ,

    Source

    Blood 111:3 2008 Feb 01 pg 1428-36

    MeSH

    Cell Line
    Cell Survival
    Cytotoxicity, Immunologic
    Enzyme Inhibitors
    GPI-Linked Proteins
    HLA Antigens
    Histocompatibility Antigens Class I
    Histone Deacetylase Inhibitors
    Histone Deacetylases
    Humans
    Intracellular Signaling Peptides and Proteins
    Killer Cells, Natural
    Leukemia, Myeloid, Acute
    Ligands
    Membrane Proteins
    NK Cell Lectin-Like Receptor Subfamily K
    Receptors, Immunologic
    Receptors, Natural Killer Cell
    Sensitivity and Specificity
    Solubility
    Up-Regulation
    Valproic Acid

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    17993609

    Citation

    Diermayr, Stefan, et al. "NKG2D Ligand Expression in AML Increases in Response to HDAC Inhibitor Valproic Acid and Contributes to Allorecognition By NK-cell Lines With Single KIR-HLA Class I Specificities." Blood, vol. 111, no. 3, 2008, pp. 1428-36.
    Diermayr S, Himmelreich H, Durovic B, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood. 2008;111(3):1428-36.
    Diermayr, S., Himmelreich, H., Durovic, B., Mathys-Schneeberger, A., Siegler, U., Langenkamp, U., ... Wodnar-Filipowicz, A. (2008). NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood, 111(3), pp. 1428-36.
    Diermayr S, et al. NKG2D Ligand Expression in AML Increases in Response to HDAC Inhibitor Valproic Acid and Contributes to Allorecognition By NK-cell Lines With Single KIR-HLA Class I Specificities. Blood. 2008 Feb 1;111(3):1428-36. PubMed PMID: 17993609.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. AU - Diermayr,Stefan, AU - Himmelreich,Heike, AU - Durovic,Bojana, AU - Mathys-Schneeberger,Arina, AU - Siegler,Uwe, AU - Langenkamp,Ulrich, AU - Hofsteenge,Jan, AU - Gratwohl,Alois, AU - Tichelli,André, AU - Paluszewska,Monika, AU - Wiktor-Jedrzejczak,Wieslaw, AU - Kalberer,Christian P, AU - Wodnar-Filipowicz,Aleksandra, Y1 - 2007/11/09/ PY - 2007/11/13/pubmed PY - 2008/3/28/medline PY - 2007/11/13/entrez SP - 1428 EP - 36 JF - Blood JO - Blood VL - 111 IS - 3 N2 - This study exploited alloreactivity of natural killer (NK) cells for augmenting the recognition of human acute myeloid leukemia (AML). To circumvent the inhibitory effect of killer immunoglobulin receptor (KIR) signaling, we generated NK-cell lines with single KIR specificities for major human leukocyte antigen (HLA) class I allotypes. We demonstrated efficient cytolysis of KIR-HLA class I-mismatched primary AML blasts even at low effector-to-target ratios. To define the impact of tumor-associated activating NKG2D-ligands (NKG2D-L), 66 AML patients at diagnosis were analyzed. NKG2D-L were selectively expressed on monoblastic cells in AML M4 and M5 yet absent or weakly expressed on myeloblastic cells in all AML subtypes. Paucity of cell-surface NKG2D-L was not the result of shedding because levels of soluble ULBP1 ligand measured in AML plasma were in the normal range. Notably, purified NKG2D-L(+) monoblastic cells were more susceptible to NK-mediated killing than NKG2D-L(-) myeloblastic cells. Accordingly, induction of cell-surface NKG2D-L by treatment with the histone deacetylase inhibitor, valproic acid, rendered cells more sensitive to NK cytolysis. These data suggest that adoptive transfer of selected populations of alloreactive HLA class I-mismatched NK cells in combination with pharmacologic induction of NKG2D-L merits clinical evaluation as novel approaches to immunotherapy of human AML. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/17993609/NKG2D_ligand_expression_in_AML_increases_in_response_to_HDAC_inhibitor_valproic_acid_and_contributes_to_allorecognition_by_NK_cell_lines_with_single_KIR_HLA_class_I_specificities_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=17993609 DB - PRIME DP - Unbound Medicine ER -