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High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

B. Maurer, H. Nivarthi, B. Wingelhofer, HTT. Pham, M. Schlederer, T. Suske, R. Grausenburger, AI. Schiefer, M. Prchal-Murphy, D. Chen, S. Winkler, O. Merkel, C. Kornauth, M. Hofbauer, B. Hochgatterer, G. Hoermann, A. Hoelbl-Kovacic, J....

. 2020 ; 105 (2) : 435-447. [pub] 20200131

Language English Country Italy

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21020794

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 therapy 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 memory CD8+ T-lymphocyte characteristics. Histopathology and mRNA expression 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 target. 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, defining both STAT5 molecules as targets for therapeutic intervention.

Biomodels Austria University of Veterinary Medicine Vienna Vienna Austria

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Vienna Austria

Central European Institute of Technology Center of Molecular Medicine Masaryk University Brno Czech Republic

Department 1 of Internal Medicine Center for Integrated Oncology University of Cologne Cologne Germany

Department of Chemistry University of Toronto Mississauga Mississauga Ontario Canada

Department of Clinical Pathology Karl Landsteiner University of Health Sciences St Poelten Austria

Department of Clinical Pathology Medical University of Vienna Vienna Austria

Department of Internal Medicine 1 Division of Hematology and Hemostaseology and Ludwig Boltzmann Cluster Oncology Medical University of Vienna Vienna Austria

Department of Internal Medicine Hematology and Oncology Faculty of Medicine Masaryk University and University Hospital Brno Brno Czech Republic

Department of Laboratory Medicine Medical University of Vienna Vienna Austria

IFA Tulln University of Natural Resources and Applied Life Sciences Tulln Austria

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna Vienna Austria

Institute of Laboratory Animal Science University of Veterinary Medicine Vienna Vienna Austria

Institute of Medical Biochemistry University of Veterinary Medicine Vienna Vienna Austria

Institute of Pathology and Microbiology Wilheminenspital Vienna Austria

Institute of Pharmacology and Toxicology University of Veterinary Medicine Vienna Vienna Austria

Karl Landsteiner Institute of Dermatological Research St Poelten Austria and Department of Dermatology and Venereology Karl Landsteiner University for Health Sciences St Poelten Austria

Ludwig Boltzmann Institute for Cancer Research Vienna Austria

Medical University of Vienna Vienna Austria

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

References provided by Crossref.org

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$a 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 therapy 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 memory CD8+ T-lymphocyte characteristics. Histopathology and mRNA expression 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 target. 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, defining both STAT5 molecules as targets for therapeutic intervention.
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