Access through your institution Buy or subscribe 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

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. _Ex vivo_ drug sensitivity of BM blast cells from the index patient sampled at relapse was assessed against a

comprehensive set of 264 approved and investigational drugs representing both targeted and chemotherapeutic drugs as previously described.11 In short, the drugs were pre-plated in 384-well

plates over a 10 000-fold concentration range (for example, 1–10 000 nM), with 10 000 cells added to each well. After a 3-day incubation at 37 °C, cell viability was measured using the

CellTiter-Glo reagent (Promega, Madison, WI, USA). Dose–response curves for each drug were generated for the patient cells and BM mononuclear cell fractions from three healthy donors, which

served as controls. Results from the assay showed that the index patient blast cells were sensitive to the pan-BCL-2 family protein inhibitor navitoclax (EC50 81.9 nM) as well as to

corticosteroids and mitogen-activated protein kinase kinase (MEK) inhibitors (Figure 2c). The blasts did not display sensitivity (EC50 ⩾1 μM) to Janus kinase (JAK) inhibitors (ruxolitinib

and tofacitinib), RAC-alpha serine/threonine-protein kinase (AKT1) inhibitors (MK-2220), phosphoinisitide 3-kinase (PI3K) inhibitors (for example, idelalisib and XL147), dual inhibitors of

PI3K and mammalian target of rapamycin (MTOR) (PF-04691502 and dactolisib) and rapalogs (temsirolimus and everolimus). This is a preview of subscription content, access via your institution

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HYPOXIC VIABILITY OF GLIOMA CELLS * Soo Jung Park * , Hyunmi Kim *  … Ilo Jou _Acta Neuropathologica Communications_ Open Access 17 September 2019 * STRUCTURAL AND FUNCTIONAL CONSEQUENCES OF

THE STAT5BN642H DRIVER MUTATION * Elvin D. de Araujo * , Fettah Erdogan *  … Patrick T. Gunning _Nature Communications_ Open Access 07 June 2019 ACCESS OPTIONS Access through your

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our FAQs * Contact customer support REFERENCES * Yamada K, Ariyoshi K, Onishi M, Miyajima A, Hayakawa F, Towatari M _et al_. Constitutively active STAT5A and STAT5B _in vitro_ and _in vivo_:

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immunoprecipitation-based gene identification. _J Biol Chem_ 2004; 279: 54724–54730. Article  CAS  Google Scholar  Download references 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. AUTHOR

INFORMATION Author notes * M Kontro and H Kuusanmäki: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * 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 * 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 * Department of Hematology, Oncology, and Tumor Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany T Burmeister * Department of Clinical Science, Hematology

Section, University of Bergen, Bergen, Norway Ø Bruserud & B T Gjertsen * Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway Ø Bruserud 

& B T Gjertsen * Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University, Aachen, Germany T H Brümmendorf * Department of

Clinical Hematology, Turku University Central Hospital, University of Turku, Turku, Finland M Itälä-Remes * Tampere Center for Child Health Research, University of Tampere School of Medicine

and Tampere University Hospital, Tampere, Finland O Lohi * Department of Clinical Chemistry and TYKSLAB, Turku University Central Hospital, University of Turku, Turku, Finland T Lundán *

Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland K Vettenranta * Institute of Biomedicine,

University of Helsinki, Helsinki, Finland C A Heckman Authors * M Kontro View author publications You can also search for this author inPubMed Google Scholar * H Kuusanmäki View author

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publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to C A Heckman. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no

conflict of interest. ADDITIONAL INFORMATION 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. Supplementary Information accompanies this paper on the Leukemia website

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THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 27 February 2014 * Issue Date: August 2014 * DOI: https://doi.org/10.1038/leu.2014.89 SHARE THIS ARTICLE

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