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Type of publication: Journal Article
Type of document: Full Paper

Year: 2020

Authors: Maurer, B; Nivarthi, H; Wingelhofer, B; Pham, HTT; Schlederer, M; Suske, T; Grausenburger, R; Schiefer, AI; Prchal-Murphy, M; Chen, D; Winkler, S; Merkel, O; Kornauth, C; Hofbauer, M; Hochgatterer, B; Hoermann, G; Hoelbl-Kovacic, A; Prochazkova, J; Lobello, C; Cumaraswamy, AA; Latzka, J; Kitzwögerer, M; Chott, A; Janikova, A; Pospíšilova, Š; Loizou, JI; Kubicek, S; Valent, P; Kolbe, T; Grebien, F; Kenner, L; Gunning, PT; Kralovics, R; Herling, M; Müller, M; Rülicke, T; Sexl, V; Moriggl, R

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

Source: Haematologica. 2020; 105(2):435-447



Authors Vetmeduni Vienna:

Grausenburger Reinhard
Grebien Florian
Hölbl-Kovacic Andrea
Kenner Lukas
Kolbe Thomas
Maurer Barbara
Moriggl Richard
Müller Mathias
Pham Ha
Prchal-Murphy Michaela
Rülicke Thomas
Sexl Veronika
Suske Tobias
Wingelhofer Bettina

Vetmed Research Units
Institut für In-vivo und In-vitro-Modelle
Institute for Medical Biochemistry
Institute of Pharmacology and Toxicology
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics
Institute of Animal Breeding and Genetics, Unit of Molecular Genetics


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 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.Copyright© 2020 Ferrata Storti Foundation.


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