title: Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias.
abstract: Natural killer (NK) cell-mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow-derived CD34(+) progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-gamma, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell-mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.
authors.affiliation: Department of Research, Experimental Hematology, Basel University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland.
authors.forename: Pegah
authors.initials: P
authors.lastname: Nowbakht
authors.forename: Mihai-Constantin S
authors.initials: MC
authors.lastname: Ionescu
authors.forename: Andreas
authors.initials: A
authors.lastname: Rohner
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kalberer
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Rossy
authors.forename: Lucia
authors.initials: L
authors.lastname: Mori
authors.forename: David
authors.initials: D
authors.lastname: Cosman
authors.forename: Gennaro
authors.initials: G
authors.lastname: De Libero
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wodnar-Filipowicz
mesh_terms: D000208:Acute Disease; D016022:Case-Control Studies; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D009000:Monocytes / Q000473:pathology*; D022423:Myeloid Cells / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic / Q000235:genetics*; D055607:Receptors, Natural Killer Cell
chemical_list: C527085:KLRK1 protein, human; D008024:Ligands; C112260:NCR1 protein, human; C112837:NCR2 protein, human; C431710:NCR3 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; D055629:Natural Cytotoxicity Triggering Receptor 2; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell