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

Maxime Boy, Valeria Bisio, Lin-Pierre Zhao, Fabien Guidez, Bérénice Schell, Emilie Lereclus, Guylaine Henry, Juliette Villemonteix, Fernando Rodrigues-Lima, Katia Gagne, Christelle Retiere, Lise Larcher, Rathana Kim, Emmanuelle Clappier, Marie Sebert, Arsène Mekinian, Olivier Fain, Anne Caignard, Marion Espeli, Karl Balabanian, Antoine Toubert, Pierre Fenaux, Lionel Ades and Nicolas Dulphy ()
Additional contact information
Maxime Boy: INSERM UMR_S1160
Valeria Bisio: INSERM UMR_S1160
Lin-Pierre Zhao: INSERM UMR_S1160
Fabien Guidez: Hôpital Saint-Louis
Bérénice Schell: INSERM UMR_S1160
Emilie Lereclus: INSERM UMR_S1160
Guylaine Henry: Hôpital Saint-Louis
Juliette Villemonteix: Hôpital Saint-Louis
Fernando Rodrigues-Lima: CNRS UMR 8251
Katia Gagne: Centre Pays de la Loire
Christelle Retiere: Centre Pays de la Loire
Lise Larcher: Hôpital Saint-Louis
Rathana Kim: Hôpital Saint-Louis
Emmanuelle Clappier: Hôpital Saint-Louis
Marie Sebert: Hôpital Saint-Louis
Arsène Mekinian: Hôpital Saint-Antoine, AP-HP
Olivier Fain: Hôpital Saint-Antoine, AP-HP
Anne Caignard: INSERM UMR_S1160
Marion Espeli: INSERM UMR_S1160
Karl Balabanian: INSERM UMR_S1160
Antoine Toubert: INSERM UMR_S1160
Pierre Fenaux: Hôpital Saint-Louis
Lionel Ades: Hôpital Saint-Louis
Nicolas Dulphy: INSERM UMR_S1160

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36193-w

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