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

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.

• Authors: Barbara Maurer, Harini Nivarthi, Bettina Wingelhofer, Ha Thi Thanh Pham, Michaela Schlederer, Tobias Suske, Reinhard Grausenburger, Ana-Iris Schiefer, Michaela Prchal-Murphy, Doris Chen, Susanne Winkler, Olaf Merkel, Christoph Kornauth, Maximilian Hofbauer, Birgit Hochgatterer, Gregor Hoermann, Andrea Hoelbl-Kovacic, Jana Prochazkova, Cosimo Lobello, Abbarna A Cumaraswamy, Johanna Latzka, Melitta Kitzwögerer, Andreas Chott, Andrea Janikova, Šárka Pospíšilova, Joanna I Loizou, Stefan Kubicek, Peter Valent, Thomas Kolbe, Florian Grebien, Lukas Kenner, Patrick T Gunning, Robert Kralovics, Marco Herling, Mathias Müller, Thomas Rülicke, Veronika Sexl, Richard Moriggl
• Journal: Haematologica (Haematologica) Vol. 105 Issue 2 Pg. 435-447 ( 2020) ISSN: 1592-8721 [Electronic] Italy
• PMID: 31123029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2020 Ferrata Storti Foundation.

Chemical References

• Cytokines
• STAT5 Transcription Factor
• STAT5A protein, human
• Tumor Suppressor Proteins

Topics

• Animals
• CD8-Positive T-Lymphocytes (metabolism)
• Cytokines
• Humans
• Leukemia
• Lymphoma, T-Cell, Peripheral (genetics)
• Mice
• STAT5 Transcription Factor (genetics, metabolism)
• Tumor Suppressor Proteins