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Non-Hodgkin Lymphoma
High activation of STAT5A drives peripheral T-cell lymphoma and leukemia
Barbara Maurer,1,2,3 Harini Nivarthi,4 Bettina Wingelhofer,1,2 Ha Thi Thanh Pham,1,2 Michaela Schlederer,1,5 Tobias Suske,2 Reinhard Grausenburger,3
Ana-Iris Schiefer,5 Michaela Prchal-Murphy,3 Doris Chen,4 Susanne Winkler,1 Olaf Merkel,5 Christoph Kornauth,5 Maximilian Hofbauer,1 Birgit Hochgatterer,1 Gregor Hoermann,6 Andrea Hoelbl-Kovacic,3 Jana Prochazkova,4 Cosimo Lobello,7 Abbarna A. Cumaraswamy,8 Johanna Latzka,9 Melitta Kitzwögerer,10 Andreas Chott,11 Andrea Janikova,12 Šárka Pospíšilova,7,12 Joanna I. Loizou,4 Stefan Kubicek,4 Peter Valent,13 Thomas Kolbe,14,15 Florian Grebien,1,16 Lukas Kenner,1,5,17 Patrick T. Gunning,7 Robert Kralovics,4 Marco Herling,18 Mathias Müller,2 Thomas Rülicke,19 Veronika Sexl3 and Richard Moriggl1,2,20
1Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; 2Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; 3Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria; 4CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 5Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria; 6Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria; 7Central European Institute of Technology (CEITEC), Center of Molecular Medicine, Masaryk University, Brno, Czech Republic; 8Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada; 9Karl Landsteiner Institute of Dermatological Research, St. Poelten, Austria and Department of Dermatology and Venereology, Karl Landsteiner University for Health Sciences, St. Poelten, Austria; 10Department of Clinical Pathology, Karl Landsteiner University of Health Sciences, St. Poelten, Austria; 11Institute of Pathology and Microbiology, Wilheminenspital, Vienna, Austria; 12Department of Internal Medicine – Hematology and Oncology, Faculty of Medicine Masaryk University and University Hospital Brno, Brno, Czech Republic; 13Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria; 14Biomodels Austria, University of Veterinary Medicine Vienna, Vienna, Austria; 15IFA-Tulln, University of Natural Resources and Applied Life Sciences, Tulln, Austria; 16Institute of Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria; 17Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria; 18Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; 19Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria and 20Medical University of Vienna, Vienna, Austria
ABSTRACT
Recurrent gain-of-function mutations in the transcription factors STAT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted ther- apy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8+ T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated mem- ory CD8+ T-lymphocyte characteristics. Histopathology and mRNA expres- sion profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic tar- get. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia in vivo. We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defin- ing both STAT5 molecules as targets for therapeutic intervention.
Ferrata Storti Foundation
Haematologica 2018 Volume 105(2):435-447
Correspondence:
RICHARD MORIGGL
richard.moriggl@vetmeduni.ac.at
Received: January 18, 2019. Accepted: May 21, 2019. Pre-published: May 23, 2019.
doi:10.3324/haematol.2019.216986
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/435
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