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. doi: 10.1182/blood-2007-07-101311. Epub 2007 Nov 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Survival
  • Cytotoxicity, Immunologic / immunology
  • Enzyme Inhibitors / pharmacology
  • GPI-Linked Proteins
  • HLA Antigens / immunology*
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology*
  • Leukemia, Myeloid, Acute / blood
  • Leukemia, Myeloid, Acute / immunology
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Ligands
  • Membrane Proteins / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Sensitivity and Specificity
  • Solubility
  • Up-Regulation / drug effects
  • Valproic Acid / analogs & derivatives*
  • Valproic Acid / pharmacology


  • Enzyme Inhibitors
  • GPI-Linked Proteins
  • HLA Antigens
  • Histocompatibility Antigens Class I
  • Histone Deacetylase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • KLRK1 protein, human
  • Ligands
  • MHC class I-related chain A
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • ULBP1 protein, human
  • valpronic acid
  • Valproic Acid
  • Histone Deacetylases