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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3615-3622.
Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-07-2585.
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IMMUNOBIOLOGY
Ligands for natural killer cell–activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias
Pegah Nowbakht,
Mihai-Constantin S. Ionescu,
Andreas Rohner,
Christian P. Kalberer,
Emmanuel Rossy,
Lucia Mori,
David Cosman,
Gennaro De Libero, and
Aleksandra Wodnar-Filipowicz
From the Department of Research, Experimental Hematology and Experimental Immunology, University Hospital Basel, Switzerland; and Amgen Washington Inc, Seattle.
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- , 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.
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