title: Hydroxyurea upregulates NKG2D ligand expression in myeloid leukemia cells synergistically with valproic acid and potentially enhances susceptibility of leukemic cells to natural killer cell-mediated cytolysis.
abstract: Valproic acid (VPA), a histone deacetylase inhibitor, upregulates NKG2D ligands (NKG2DLs) on some monocytic and lymphoid leukemic cells. However, its effect on myeloid leukemia cells and synergistic agents that can augment the effect of VPA remains unknown. Of the various myeloid cell lines examined, OUN-1, a chronic myelogenous leukemia cell line, showed the most prominent upregulation of MICA/B and ULBP2 in response to VPA. The NKG2DL upregulation was observed only in leukemic cells without apoptosis and the effect was abrogated by pretreatment of cells with caffeine, an inhibitor of ATM/ATR. Several activators of ATM/ATR were screened for their effect on NKG2DL expression, but only hydroxyurea (HU) efficiently upregulated both MICA/B and ULPB2 expression on the cell line. VPA and HU synergistically upregulated the NKG2DLs on OUN-1 cells as well as primary leukemic cells from some patients with acute myeloid leukemia. The upregulation of NKG2DLs by VPA and/or HU was associated with increased transcription of each NKG2DL gene. OUN-1 cells treated with VPA + HU were more susceptible to killing by natural killer (NK) cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the treatment of NK cells with anti-NKG2D monoclonal antibodies. The same concentrations of VPA and HU did not affect the cytotoxicity of NK cells against OUN-1 cells. These data suggest that VPA and HU might enhance the NK cell-mediated antileukemia effect by increasing the susceptibility of myeloid leukemic cells to NK cells.
authors.affiliation: Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Xuzhang
authors.initials: X
authors.lastname: Lu
authors.forename: Kinya
authors.initials: K
authors.lastname: Ohata
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kondo
authors.forename: J Luis
authors.initials: JL
authors.lastname: Espinoza
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Qi
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
mesh_terms: D002110:Caffeine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004357:Drug Synergism; D058851:GPI-Linked Proteins; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology*; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C423230:ULBP2 protein, human; D002110:Caffeine; D014635:Valproic Acid; D006918:Hydroxyurea