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

Genes & Immunity volume 16, pages 71–82 (2015)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from the Red de Investigación Renal (REDinREN RD12/0021), Spain, and the Spanish Fondo de Investigaciones Sanitarias-Fondos FEDER European Union (FIS PI12/02587) del Plan Nacional de I+D+I 2008-2011. ABR was supported by a Severo Ochoa fellowship (FICYT, Consejería de Educación y Ciencia del Principado de Asturias, Spain).

Author Contributions

ABR, BS-A and CL-L designed the study. ABR and AFS did the research. VM-P, RMR and MFF provided samples. ABR and BS-A collected, analyzed and interpreted the results. ABR, BS-A and CL-L wrote the manuscript.

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  1. C Lopez-Larrea and B Suarez-Alvarez: CL-L and BS-A share senior authorship.

Authors and Affiliations

  1. Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain

    A Baragaño Raneros, R M Rodriguez & C Lopez-Larrea

  2. Area of Cell Therapy, Hospital Reina Sofía, Córdoba, Spain

    V Martín-Palanco

  3. Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, Oviedo, Spain

    A F Fernandez & M F Fraga

  4. Fundación Renal ‘Iñigo Álvarez de Toledo’, Madrid, Spain

    C Lopez-Larrea

  5. Cellular Biology of Renal Diseases Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain

    B Suarez-Alvarez

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  1. A Baragaño Raneros
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Baragaño Raneros, A., Martín-Palanco, V., Fernandez, A. et al. Methylation of NKG2D ligands contributes to immune system evasion in acute myeloid leukemia. Genes Immun 16, 71–82 (2015). https://doi.org/10.1038/gene.2014.58

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