Abstract
Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignancy originated from a myeloid lineage of bone marrow cells with median overall survival of 8.5 months and 24% 5-year overall survival according to National Cancer Institute in the USA [1, 2]
In this study focused on myeloid leukemias, 3-year cumulative incidence of relapse in patients with MICA mismatched vs MICA matched graft was higher for patients with a matched graft (20% for mismatched versus 35% for matched graft) [123]
Because natural killer (NK) activity is based on the balance of inhibitory and activating signals mediated by an interaction between ligands and receptors, AML cells downregulate some ligands for one of the most critical activating receptor NKG2D
Summary
NKG2D receptor recognizes and binds multiple ligand families, and upon ligand’s engagement it interacts with adapter dimer DAP10, which triggers activation signal leading to cell-mediated cytotoxicity (degranulation), co-stimulation of cytokine production, playing an important role in the tumorous and infected cells elimination [18, 22, 23]. NKG2D ligands are expressed on healthy conditions, on proliferative cells like embryonic cells [31], myeloid progenitors [32], normal intestinal epithelial cells [33], or cells of repairing tissue [34] The mechanisms protecting these cells against NK cell attack are not fully known. The polymorphism of NKG2D ligands genes affects susceptibility to different diseases [37], disease severity [38], transplantation outcome (organ or HSCT), and serves as a risk factor [39] and/or as protective factor for cancer [40]
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