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Haematologica. 2019 May 23. pii: haematol.2019.216986. doi: 10.3324/haematol.2019.216986. [Epub ahead of print]

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

Author information

1
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Austria.
2
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
3
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Austria.
4
Department of Clinical Pathology, Medical University of Vienna, Austria.
5
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
6
Department of Laboratory Medicine, Medical University of Vienna, Austria.
7
Central European Institute of Technology Center of Molecular Medicine, Masaryk University, Brno.
8
Department of Chemistry, University of Toronto Mississauga, Mississauga, Ontario, Canada.
9
Dept. of Dermatology & Venereology, Karl Landsteiner Univ for Health Sciences, St. Pölten.
10
Dept. of Clinical Pathology, Karl Landsteiner University of Health Sciences,St. Pölten, Austria.
11
Institute of Pathology and Microbiology, Wilheminenspital, Vienna, Austria.
12
Dept. of Internal Medicine,Hematology,Oncology, Masaryk University, Brno, Czech Republic.
13
Central European Institute of Technology, Center of Molecular Medicine Masaryk University, Brno.
14
Dept. of Internal Medicine I, Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria.
15
Biomodels Austria, University of Veterinary Medicine Vienna, Austria.
16
Institute of Medical Biochemistry, University of Veterinary Medicine Vienna, Austria.
17
Dept.of Internal Medicine, Center for Integrated Oncology, University of Cologne, Germany.
18
Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Austria.
19
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria richard.moriggl@vetmeduni.ac.at.

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). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for peripheral T-cell lymphoma, 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 high activity levels developed a lethal disease resembling human peripheral T-cell lymphoma. 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 analysis and mRNA expression profiles revealed close correlation with distinct human peripheral T-cell lymphoma subtypes. Pronounced STAT5 expression and activity in patient samples of different subsets underlines the relevance of JAK/STAT as 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 peripheral T-cell lymphoma development, defining both STAT5 molecules as targets for therapeutic intervention.

KEYWORDS:

Hematopoiesis; Lymphocytes; Lymphoproliferative Disorders; PTCL; STAT5

PMID:
31123029
DOI:
10.3324/haematol.2019.216986
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