Demethylating treatment suppresses natural killer cell cytolytic activity

DNA demethylation and histone H3K9 acetylation determine the active transcription of the NKG2D gene in human CD8+T and NK cells

“…Azacytidine impairs NK cell function by overexpression of inhibitory KIR receptors, whereas decitabine enhances IFN-γ production and NK cell-mediated cytotoxicity. 38,39 Similarly, treatments with HDAC inhibitors (VPA and SAHA) inhibit NK cell cytotoxicity by reducing expression of activating receptor Nkp30 and Nkp46 as well as impairing granule exocytosis. 40 However, the modulation of the NKG2D-mediated NK cell cytotoxicity has not been analyzed in depth.…”

Lack of expression of inhibitory KIR3DL1 receptor in patients with natural killer cell-type lymphoproliferative disease of granular lymphocytes

“…15 Recently, it has been demonstrated that DNA methylation plays an important role in the regulation of KIR gene expression. [16][17][18] CpG dinucleotides located upstream of the translation initiation codon of each KIR gene (KIR2DL3, 3DL2, 3DL1) are either densely methylated in the case of repressed KIR genes or demethylated in expressed KIR genes. Expression of formerly silenced KIR genes can be readily induced using a demethylating agent.…”

5-Azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

“…These findings are in line with previous reports that the compounds produced hypomethylation at levels lower than that required to affect cell viability. 10,39 Demethylating agents have also been reported to modify antibody-independent NK lytic activity, 45,46 possibly through changes in chromatin structure. 19,47,48 Treatment of primary human NK cells or NK cell lines with micromolar quantities of 5-azacytidine suppressed cytolytic activity, resulting in decreased lysis of NK-sensitive cytotoxic to the implanted AML cells.…”

“…Animal experiments were conducted in an AALAC (Association for Assessment of Laboratory Animal Care) cell lines. 45,46 Loss of antibody-independent NK killing activity was associated with overexpression of inhibitory KIRs (killer immunoglobulin-like regulatory receptors) and impaired release of perforin and granzymes. 45 Interestingly, in the current study, we found that sub-micromolar concentrations of 5-azacytidine actually improved lintuzumab-mediated ADCC against AML target cells.…”