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Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia

Leukemia volume 30, pages 1204–1208 (2016)Cite this article

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Large granular lymphocyte (LGL) leukemia is a rare clonal disease characterized by a persistent increase in the number of CD8+ cytotoxic T cells or CD16/56+ natural killer (NK) cells.1 Patients are prone to recurrent infections and often suffer from severe cytopenias and autoimmune diseases that are thought to be mediated by cytotoxic LGL lymphocytes. LGL leukemia is believed to begin as an antigen-driven immune response followed by the constitutive activation of cytotoxic T lymphocytes or NK cells. Overall, studies have highlighted the dysregulation of different apoptotic pathways (for example, sphingolipid and FAS/FAS ligand) and the activation of survival signaling pathways (for example, PI3K/AKT and RAS).1

Previously, activating mutations in the Src-like homology 2 (SH2)-domain of the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 40% of LGL leukemia patients.2 These findings have later been validated in other cohorts, reporting STAT3 mutation frequency to be even up to 73% in selected patient groups.3 Interestingly, aberrant STAT3 signaling is seen in almost all LGL leukemia patients,4 indicating that the JAK/STAT pathway is activated through other mechanisms as well. In addition to LGL leukemia, activating somatic STAT3 mutations have recently been found in other diseases including T-, NK- and B-cell lymphomas,5, 6, 7 hepatocellular adenomas8 and chronic lymphoproliferative disorders of NK cells.9 In a clinical phase II study, it was shown that the strongest activating STAT3 mutation, Y640F, predicted therapeutic response to immunosuppressive methotrexate in LGL leukemia, as all patients with this mutation responded to therapy after at least 4 cycles of methotrexate.10

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Acknowledgements

This work was supported by the Academy of Finland, the Finnish Cancer Institute, the Finnish Cancer Societies, Sigrid Juselius Foundation, Instrumentarium Science Foundation, State funding for university-level health research in Finland, European Regional Development Fund, Swedish Cultural Foundation, Blood Disease Foundation, Signe and Ane Gyllenberg foundation and the Finnish Cultural Foundation. Work of JPM and MJC was supported in part by the National Institutes for Health (grants 2K24HL077522, R01 CA127264A and R01AI085578). The work of TPL and TO was supported by the National Cancer Institute (RO1 CA 098472) and the National Institutes for Health (T32CA009109). Personnel at the Hematology Research Unit Helsinki and FIMM are acknowledged for their expert clinical and technical assistance.

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Authors and Affiliations

  1. Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland

    E Andersson, H Kuusanmäki, S Bortoluzzi, H Rajala & S Mustjoki

  2. Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland

    E Andersson, H Rajala, A Laasonen & S Mustjoki

  3. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    H Kuusanmäki, S Lagström, A Parsons, A van Adrichem, S Eldfors, P Ellonen & C Heckman

  4. University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA

    T Olson & T P Loughran

  5. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    M J Clemente & J P Maciejewski

  6. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland

    S Mustjoki

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  1. E Andersson
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  2. H Kuusanmäki
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  9. T Olson
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  10. M J Clemente
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  14. T P Loughran
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  15. J P Maciejewski
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  16. S Mustjoki
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Corresponding author

Correspondence to S Mustjoki.

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Competing interests

HR has received honoraria from Novartis. SM has received honoraria and research funding from Novartis, Pfizer and Bristol-Myers Squibb.

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Andersson, E., Kuusanmäki, H., Bortoluzzi, S. et al. Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia. Leukemia 30, 1204–1208 (2016). https://doi.org/10.1038/leu.2015.263

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