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

摘要: Large granular lymphocyte leukemia (LGLL) is characterized by somatic gain-of-function STAT3 mutations. However, the functional effects of mutations on primary LGLL cells have not been studied in detail. In this study, we show that CD8+ T isolated from mutated patients high protein levels epigenetic regulators, such as DNMT1, and are global hypermethylation. Correspondingly, treatment healthy with IL-6, IL-15, and/or MCP-1 cytokines resulted activation, increased EZH2, c-MYC, l-MYC, MAX, NFκB levels, DNA methylation, oxidative stress. Similar results were discovered KAI3 NK overexpressing STAT3Y640F STAT3G618R mutants compared to STAT3WT. Our also confirm forms a direct complex HDAC1. cells, methyltransferase (DNMT) inhibitor azacitidine abrogated activation via restored SHP1 expression. conclusion, cause hypermethylation resulting sensitivity DNMT inhibitors, which could be considered novel option for resistance standard treatments.