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Large granular lymphocyte leukemia (LGLL) is characterized by somatic gain-of-function  STAT3  mutations. However, the functional effects of  STAT3  mutations on primary LGLL cells have not been studied in detail. In this study, we show that CD8+ T cells isolated from  STAT3  mutated LGLL patients have high protein levels of epigenetic regulators, such as DNMT1, and are characterized by global hypermethylation. Correspondingly, treatment of healthy CD8+ T cells with IL-6, IL-15, and/or MCP-1 cytokines resulted in STAT3 activation, increased DNMT1, EZH2, c-MYC, l-MYC, MAX, and NFκB levels, increased DNA methylation, and increased oxidative stress. Similar results were discovered in KAI3 NK cells overexpressing gain-of-function  STAT3  Y640F  and  STAT3  G618R  mutants compared to KAI3 NK cells overexpressing  STAT3  WT . Our results also confirm that STAT3 forms a direct complex with DNMT1, EZH2, and HDAC1. In  STAT3  mutated LGLL cells, DNA methyltransferase (DNMT) inhibitor azacitidine abrogated the activation of STAT3 via restored SHP1 expression. In conclusion,  STAT3  mutations cause DNA hypermethylation resulting in sensitivity to DNMT inhibitors, which could be considered as a novel treatment option for LGLL patients with resistance to standard treatments.

STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation