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

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

  • Leukemia. 2021 Dec;35(12):3430-3443. doi: 10.1038/s41375-021-01296-0.
Daehong Kim 1 2 Giljun Park 1 2 Jani Huuhtanen 1 2 Bishwa Ghimire 3 Hanna Rajala 1 2 Richard Moriggl 4 Wing C Chan 5 Matti Kankainen 1 2 6 7 Mikko Myllymäki 1 2 Satu Mustjoki 8 9 10
Affiliations

Affiliations

  • 1 Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
  • 2 Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
  • 3 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
  • 4 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 5 Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
  • 6 Department of Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • 7 iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland.
  • 8 Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. [email protected].
  • 9 Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland. [email protected].
  • 10 iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. [email protected].
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 STAT3Y640F and STAT3G618R mutants compared to KAI3 NK cells overexpressing STAT3WT. 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.

Figures
Products