The mechanism of EZH2/H3K27me3 downregulating CXCL10 to affect CD8+ T cell exhaustion to participate in the transformation from myelodysplastic syndrome to acute myeloid leukaemia.

Abstract

Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) link to unfavourable prognoses. We explored the mechanism of enhancer of zeste homologue 2/histone H3 of lysine 27 (EZH2/H3K27me3) downregulating C-X-C motif chemokine 10 (CXCL10) to affect CD8⁺ T-cell exhaustion, participating in MDS-to-AML transformation. NHD13 mice were treated with GSK126 (EZH2 inhibitor) and CXCL10 neutralizing antibody, with transformation time, blood cell counts and CD8⁺ T cell determined. SKM-1 cells treated with short hairpin-EZH2, overexpressing-EZH2, GSK126 and CXCL10 were co-cultured with CD8⁺ T cells. EZH2, CXCL10, H3K27me3 and EZH2 levels and EZH2 enzyme activity were assessed. CD8⁺ T-cell cytotoxicity, exhaustion, apoptosis and SKM-1 cell malignant behaviours were evaluated. In vivo, EZH2 inhibition upregulated CXCL10, decelerating MDS to AML transformation and delaying CD8⁺ T-cell exhaustion. EZH2 inhibition elevated peripheral blood cells, alleviated splenomegaly, reduced CD8⁺ T cells, elevated CD8⁺ T cytotoxicity and abated CD8⁺ T-cell exhaustion in NHD13 mice. CXCL10 neutralizing antibody accelerated AML transformation by inhibiting CD8⁺ T-cell exhaustion via EZH2. In vitro, EZH2 overexpression facilitated CD8⁺ T-cell exhaustion and SKM-1 cell malignant behaviours. EZH2-mediated H3K27me3 curbed CXCL10 transcription and secretion. Collectively, EZH2/H3K27me3 downregulates CXCL10 to facilitate CD8⁺ T-cell exhaustion, accelerating transformation from MDS to AML.