Myelodysplastic Syndrome-associated TET2/IDH mutations in Natural Killer cells disrupt their anti-tumor activity

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-a. 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-? 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. Overall design: Reduced representation bisulfite sequencing analysis were performed on NK cells and T cells sorted from TET2 wt and TET2 mut MDS/CMML patients, Three TET2 mut MDS/CMML patients were chosen based on a KIR2D expression on NK cells below 25%, and a TET2 mutation VAF superior to 45% in the cell bulk at diagnosis (TET2 mut KIR low patients: MUT22, MUT27, MUT33). One TET2 mut was chosen because of aKIR2D expression on NK cells at 90% to serve as control (TET2 mut KIR high patient: MUT14) with the TET2 wt patient (TET2 wt KIR high patient: WT13).