Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation

• Published in: Nature communications Vol. 14; no. 1; pp. 588 - 14
• Main Authors: Boy, Maxime, Bisio, Valeria, Zhao, Lin-Pierre, Guidez, Fabien, Schell, Bérénice, Lereclus, Emilie, Henry, Guylaine, Villemonteix, Juliette, Rodrigues-Lima, Fernando, Gagne, Katia, Retiere, Christelle, Larcher, Lise, Kim, Rathana, Clappier, Emmanuelle, Sebert, Marie, Mekinian, Arsène, Fain, Olivier, Caignard, Anne, Espeli, Marion, Balabanian, Karl, Toubert, Antoine, Fenaux, Pierre, Ades, Lionel, Dulphy, Nicolas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 45/15; 45/23; 45/88; 631/250/1619/382; 631/250/2520; 631/250/580/1884; 631/67/1990/1673; Acute myeloid leukemia; Azacitidine - pharmacology; Azacytidine; Cloning; Cytolytic activity; Cytotoxicity; Deoxyribonucleic acid; Dioxygenases - metabolism; Disorders; DNA; DNA methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenetics; Gene expression; Genotypes; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunoglobulin-like receptors; Killer cell immunoglobulin-like receptors; Killer Cells, Natural; Leukemia; Life Sciences; Methylation; multidisciplinary; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - metabolism; Natural killer cells; Perforin; Receptors, KIR - genetics; Science; Science (multidisciplinary); Toxicity; Tumor necrosis factor-α; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36193-w

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders, representing high risk of progression to acute myeloid leukaemia, and frequently associated to somatic mutations, notably in the epigenetic regulator TET2 . Natural Killer (NK) cells play a role in the anti-leukemic immune response via their cytolytic activity. Here we show that patients with MDS clones harbouring mutations in the TET2 gene are characterised by phenotypic defects in their circulating NK cells. Remarkably, NK cells and MDS clones from the same patient share the TET2 genotype, and the NK cells are characterised by increased methylation of genomic DNA and reduced expression of Killer Immunoglobulin-like receptors (KIR), perforin, and TNF-α. In vitro inhibition of TET2 in NK cells of healthy donors reduces their cytotoxicity, supporting its critical role in NK cell function. Conversely, NK cells from patients treated with azacytidine (#NCT02985190; https://clinicaltrials.gov/ ) show increased KIR and cytolytic protein expression, and IFN-γ production. Altogether, our findings show that, in addition to their oncogenic consequences in the myeloid cell subsets, TET2 mutations contribute to repressing NK-cell function in MDS patients. Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.