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

ABSTRACT: 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 KA

SUBMITTER: Kim D 

PROVIDER: S-EPMC8632689 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature