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

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Kim , D , Park , G , Huuhtanen , J , Ghimire , B , Rajala , H , Moriggl , R , Chan , W C , Kankainen , M , Myllymäki , M & Mustjoki , S 2021 , ' STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation ' , Leukemia , vol. 35 , no. 12 , pp. 3430-3443 . https://doi.org/10.1038/s41375-021-01296-0

Title: STAT3 activation in large granular lymphocyte leukemia is associated with cytokine signaling and DNA hypermethylation
Author: Kim, Daehong; Park, Giljun; Huuhtanen, Jani; Ghimire, Bishwa; Rajala, Hanna; Moriggl, Richard; Chan, Wing C.; Kankainen, Matti; Myllymäki, Mikko; Mustjoki, Satu
Contributor organization: Department of Clinical Chemistry and Hematology
Medicum
Hematologian yksikkö
HUS Comprehensive Cancer Center
Department of Oncology
HUSLAB
TRIMM - Translational Immunology Research Program
Research Programs Unit
Institute for Molecular Medicine Finland
University of Helsinki
Department of Medical and Clinical Genetics
Digital Precision Cancer Medicine (iCAN)
Date: 2021-12
Language: eng
Number of pages: 14
Belongs to series: Leukemia
ISSN: 0887-6924
DOI: https://doi.org/10.1038/s41375-021-01296-0
URI: http://hdl.handle.net/10138/340467
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 NF kappa B 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.
Subject: OXIDATIVE STRESS
NATURAL-KILLER
MUTATIONS
PATHOGENESIS
INFLAMMATION
GENE
METHYLTRANSFERASE
TRANSCRIPTION
METHYLATION
INSTABILITY
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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