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

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.

Glutathione safeguards TET‐dependent DNA demethylation and is critical for the acquisition of totipotency and pluripotency during preimplantation development

“…Having tested the role of GSH in improving 5hmC formation and DNA demethylation, we next attempted to determine if TET enzymatic activity is indispensable for GSH‐induced DNA demethylation, given that GSH did not affect expression levels of Tets (Figure S4A,B). To this end, we used dimethyloxalyl glycine (DMOG), a cell‐permeable competitor of α‐ketoglutarate (α‐KG), to inhibit the enzymatic activity of TET proteins, as previously reported 26 . We found DMOG treatment significantly attenuated the GSH‐induced DNA demethylation in both ES cells and blastocysts (Figure 4A,B).…”

“…To this end, we used dimethyloxalyl glycine (DMOG), a cell-permeable competitor of αketoglutarate (α-KG), to inhibit the enzymatic activity of TET proteins, as previously reported. 26 We found DMOG treatment significantly attenuated the GSH-induced DNA demethylation in both ES cells and blastocysts (Figure 4A,B). In line with this, the beneficial effect of GSH on ICM specification was also attenuated by TET activity inhibition (Figure 4C).…”

Immune‐monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium

“… 42 A recent study correlated the presence of TET2 mutations with reduced KIR expression and impaired NK functions, which were restored with hypomethylating agent (HMA) therapy. 114 …”

Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

“…Further, IL-1R signaling has been recently implicated as a driver of Tet2 +/− CHIP progression during aging [ 118 ]. In addition, driver mutations in TET2 may contribute to repress NK cell-mediated immune surveillance of malignant clones in the BM [ 119 ]. Together, these studies point out a continuous bi-directional inflammatory program in the aging BM niche that supports and is further driven by mutant HSPCs and their progeny, leading to remodeling of the endosteal niche while transforming the vascular niche to a selective microenvironment that favors mutated clones.…”