Maurer, Barbara, Nivarthi, Harini, Wingelhofer, Bettina ORCID: 0000-0001-6108-5245, Schlederer, Michaela, Suske, Tobias, Grausenburger, Reinhard, Schiefer, Ana-Iris, Prchal-Murphy, Michaela, Chen, Doris ORCID: 0000-0001-8835-0280, Winkler, Susanne, Merkel, Olaf, Kornauth, Christoph, Hofbauer, Maximilian, Hochgatterer, Birgit, Hoermann, Gregor ORCID: 0000-0002-7374-4380, Hoelbl-Kovacic, Andrea, Prochazkova, Jana, Lobello, Cosimo ORCID: 0000-0003-1329-2113, Cumaraswamy, Abbarna A., Latzka, Johanna, Kitzwoegerer, Melitta, Chott, Andreas, Janikova, Andrea, Pospisilova, Sarka, Loizou, Joanna, I, Kubicek, Stefan ORCID: 0000-0003-0855-8343, Valent, Peter ORCID: 0000-0003-0456-5095, Kolbe, Thomas, Grebien, Florian, Kenner, Lukas ORCID: 0000-0003-2184-1338, Gunning, Patrick T., Kralovics, Robert, Herling, Marco, Mueller, Mathias, Ruelicke, Thomas, Sexl, Veronika ORCID: 0000-0001-9363-0412 and Moriggl, Richard (2020). High activation of STAT5A drives peripheral T-cell lymphoma and leukemia. Haematologica, 105 (2). S. 435 - 448. PAVIA: FERRATA STORTI FOUNDATION. ISSN 0390-6078

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Abstract

Recurrent gain-of-function mutations in the transcription factors S7AT5A 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Maurer, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nivarthi, HariniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wingelhofer, BettinaUNSPECIFIEDorcid.org/0000-0001-6108-5245UNSPECIFIED
Schlederer, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suske, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grausenburger, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schiefer, Ana-IrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prchal-Murphy, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, DorisUNSPECIFIEDorcid.org/0000-0001-8835-0280UNSPECIFIED
Winkler, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkel, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornauth, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hofbauer, MaximilianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hochgatterer, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoermann, GregorUNSPECIFIEDorcid.org/0000-0002-7374-4380UNSPECIFIED
Hoelbl-Kovacic, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prochazkova, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lobello, CosimoUNSPECIFIEDorcid.org/0000-0003-1329-2113UNSPECIFIED
Cumaraswamy, Abbarna A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Latzka, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitzwoegerer, MelittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chott, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janikova, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pospisilova, SarkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loizou, Joanna, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubicek, StefanUNSPECIFIEDorcid.org/0000-0003-0855-8343UNSPECIFIED
Valent, PeterUNSPECIFIEDorcid.org/0000-0003-0456-5095UNSPECIFIED
Kolbe, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grebien, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kenner, LukasUNSPECIFIEDorcid.org/0000-0003-2184-1338UNSPECIFIED
Gunning, Patrick T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kralovics, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruelicke, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sexl, VeronikaUNSPECIFIEDorcid.org/0000-0001-9363-0412UNSPECIFIED
Moriggl, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-347943
DOI: 10.3324/haematol.2019.216986
Journal or Publication Title: Haematologica
Volume: 105
Number: 2
Page Range: S. 435 - 448
Date: 2020
Publisher: FERRATA STORTI FOUNDATION
Place of Publication: PAVIA
ISSN: 0390-6078
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EXPRESSION; MUTATIONS; SIGNATURES; LANDSCAPE; DIAGNOSIS; GENETICS; SYSTEMS; MODELS; SIGNAL; ALPHAMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34794

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