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Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia

Leukemia volume 28, pages 1738–1742 (2014)Cite this article

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STAT5 has an important role in many hematologic malignancies, but constitutive activation is often a secondary event.1 Mutations to STAT5B and their functional significance were recently discovered in large granular lymphocytic (LGL) leukemia.2 The mutations located in the SRC homology 2 (SH2) domain of STAT5B lead to constitutive phosphorylation of the mutant protein, increased transcriptional activity and activation of downstream target genes. However, activating mutations in STAT5B have thus far not been described in other cancers. In T-cell acute lymphoblastic leukemia (T-ALL), a complex cooperation of multiple oncogenic aberrations leads to the development of the disease.3 Approximately 9% of childhood T-ALL patients display IL7R gain-of-function mutations leading to constitutive activation of downstream targets.4 The two main pathways induced by IL7R are PI3K/AKT/MTOR and JAK/STAT5.5 In addition to mutations in IL7R, somatic JAK1 and JAK3 gain-of-function mutations are relatively prevalent in T-ALL presenting in 10.4% and 7% of adult patients, respectively.6, 7 Activating mutations to IL7R, JAK1, JAK2 or JAK3 are estimated to occur in 20–30% of all T-ALL patients.8 In naive T cells the stimulation of either JAK–STAT5 or PI3K pathway results in the induction of key anti-apoptotic factors, including B-cell lymphoma 2 (BCL-2) and myeloid cell leukemia sequence 1 (MCL1), while pro-apoptotic BCL-2 family members are inhibited.9 In T-ALL, however, the STAT5 target genes are inadequately known. Here we report the identification of activating mutations to STAT5B in T-ALL accompanied by overexpression of BCL-XL (BCL2L1) and sensitivity to pan-BCL-2 inhibitors.

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Acknowledgements

We thank the patients who participated in the study. We acknowledge personnel of the High Throughput Biomedicine Unit and Minna Suvela, Pekka Ellonen, Aino Palva, Pirkko Mattila and Henrikki Almusa from Institute for Molecular Medicine Finland (FIMM) Technology Centre, University of Helsinki for their expert technical assistance. The Finnish Cancer Societies, Blood Disease Foundation, Finnish Association of Hematology, Orion-Farmos Research Foundation, Academy of Finland, Finnish Funding Agency for Technology and Innovation, and European Regional Development Fund supported this work.

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Author notes

  1. M Kontro and H Kuusanmäki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Central Hospital Cancer Center, Helsinki, Finland

    M Kontro, H Kuusanmäki, E I Andersson, H Rajala, S Mustjoki & K Porkka

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

    H Kuusanmäki, S Eldfors, H Edgren, S Lagström, J M L Martí, M M Majumder, A Parsons, T Pemovska, O Kallioniemi & C A Heckman

  3. Department of Hematology, Oncology, and Tumor Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany

    T Burmeister

  4. Department of Clinical Science, Hematology Section, University of Bergen, Bergen, Norway

    Ø Bruserud & B T Gjertsen

  5. Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

    Ø Bruserud & B T Gjertsen

  6. Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Aachen, Germany

    T H Brümmendorf

  7. Department of Clinical Hematology, Turku University Central Hospital, University of Turku, Turku, Finland

    M Itälä-Remes

  8. Tampere Center for Child Health Research, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland

    O Lohi

  9. Department of Clinical Chemistry and TYKSLAB, Turku University Central Hospital, University of Turku, Turku, Finland

    T Lundán

  10. Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland

    K Vettenranta

  11. Institute of Biomedicine, University of Helsinki, Helsinki, Finland

    C A Heckman

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  1. M Kontro
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Correspondence to C A Heckman.

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Author contributions

MK and HK designed the study, analyzed the data and wrote the manuscript; MK collected most of the sample material; HK performed most of the experiments; SE, HE and JMLM performed sequencing data analysis; TP and MMM performed drug sensitivity testing and corresponding analysis; EIA, SL, HR, MMM and AP performed the experiments and participated in the data analysis; TB, ØB, THB, BTG, OL, TL and KV provided the patient specimens and clinical data; and OK, SM, KP and CAH conceived the study, supervised the work and wrote the manuscript. All authors contributed to and approved the final manuscript.

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Kontro, M., Kuusanmäki, H., Eldfors, S. et al. Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia. Leukemia 28, 1738–1742 (2014). https://doi.org/10.1038/leu.2014.89

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