Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia

• Published in: Genes and immunity Vol. 16; no. 1; pp. 71 - 82
• Main Authors: Baragaño Raneros, A, Martín-Palanco, V, Fernandez, A F, Rodriguez, R M, Fraga, M F, Lopez-Larrea, C, Suarez-Alvarez, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2015; Nature Publishing Group
• Subjects: 13/1; 13/31; 38/22; 38/23; 38/77; 38/90; 631/250/262; Acute myeloid leukemia; Analysis; Azacytidine; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell Line, Tumor; Cell surface; Colon cancer; Colorectal cancer; Deoxyribonucleic acid; DNA; DNA Methylation; Gene Expression; Genetic aspects; GPI-Linked Proteins - immunology; GPI-Linked Proteins - metabolism; Health aspects; Hepatocellular carcinoma; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Human Genetics; Humans; Immune system; Immunology; Innate immunity; Killer cells; Leukemia; Leukemia, Myeloid, Acute - immunology; Ligands; Lymphatic leukemia; Major histocompatibility complex; Membrane proteins; Methylation; Myeloid leukemia; NK Cell Lectin-Like Receptor Subfamily K - immunology; NK Cell Lectin-Like Receptor Subfamily K - metabolism; original-article; Physiological aspects; Protein binding; Protein families; Transcription; Tumor cell lines; Tumor cells; Tumor Escape; Spain
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2014.58

Engagement of the activating receptor NKG2D (natural killer group 2 member D) with its ligands (NKG2DL) major histocompatibility complex class I related-A and -B (MICA/B), UL-16 binding protein families (ULBPs 1–6) is important to ensure the innate immunity to tumor cells. However, these cells have developed strategies to downregulate NKG2DL expression and avoid immune recognition. We demonstrate that DNA methylation can contribute to the absence of NKG2DL expression during tumor progression. We analyzed the DNA methylation profiles for each NKG2DL by pyrosequencing in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hepatocellular carcinoma (HC), breast cancer and colon cancer cell lines. High levels of DNA methylation for NKG2DL were found in some tumor cell lines, mainly in AML cells. This hypermethylation was correlated with the absence of transcription for NKG2DL. Higher DNA methylation levels for
MICA, ULBP1
and
ULBP2
were observed in AML patients (
n
=60) compared with healthy donors (
n
=25). However, no DNA methylation for NKG2DL was found in colon cancer patients (
n
=44). Treatment with demethylating agents (5-azacytidine and 5-aza-2’-deoxycytidine) restored the expression of NKG2DL on the cell surface of AML cells, leading to an enhanced recognition by NKG2D-expressing cells. Our data suggest that NKG2DL may be aberrantly silenced by DNA methylation as a consequence of tumor development in AML patients.