Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation.
Maxime BoyValeria BisioLin-Pierre ZhaoFabien GuidezBerenice SchellEmilie LereclusGuylaine HenryJuliette VillemonteixFernando Rodrigues-LimaKatia GagneChristelle RetiereLise LarcherRathana KimEmmanuelle ClappierMarie SebertArsène MekinianOlivier FainAnne CaignardMarion EspéliKarl BalabanianAntoine ToubertPierre FenauxLionel AdesNicolas DulphyPublished in: Nature communications (2023)
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.
Keyphrases
- nk cells
- immune response
- genome wide
- dendritic cells
- bone marrow
- dna methylation
- copy number
- acute myeloid leukemia
- poor prognosis
- rheumatoid arthritis
- ejection fraction
- newly diagnosed
- gene expression
- transcription factor
- stem cells
- liver failure
- prognostic factors
- single cell
- case report
- cell free
- mesenchymal stem cells
- circulating tumor
- aortic dissection
- patient reported outcomes