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ACTIVATED STAT5 DRIVES PERIPHERAL T CELL LYMPHOMAS
Author(s): ,
Barbara Maurer
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria;Institute of Animal Breeding and Genetics,University of Veterinary Medicine Vienna,Vienna,Austria
,
Harini Nivarthi
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Michaela Prchal-Murphy
Affiliations:
Institute of Pharmacology and Toxicology,University of Veterinary Medicine Vienna,Vienna,Austria
,
Bettina Wingelhofer
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria;Institute of Animal Breeding and Genetics,University of Veterinary Medicine Vienna,Vienna,Austria
,
Doris Chen
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Susanne Winkler
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria
,
Michaela Schlederer
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria;Department of Clinical Pathology,Medical University of Vienna,Vienna,Austria
,
Ha Thi Thanh Pham
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria;Institute of Animal Breeding and Genetics,University of Veterinary Medicine Vienna,Vienna,Austria
,
Lukas Kenner
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria;Department of Clinical Pathology,Medical University of Vienna,Vienna,Austria
,
Veronika Sexl
Affiliations:
Institute of Pharmacology and Toxicology,University of Veterinary Medicine Vienna,Vienna,Austria
,
Thomas Kolbe
Affiliations:
Biomodels Austria,University of Veterinary Medicine Vienna,Vienna,Austria;IFA-Tulln,University of Natural Resources and Applied Life Sciences,Tulln,Austria
,
Robert Kralovics
Affiliations:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences,Vienna,Austria
,
Mathias Müller
Affiliations:
Institute of Animal Breeding and Genetics,University of Veterinary Medicine Vienna,Vienna,Austria
,
Thomas Rülicke
Affiliations:
Institute of Laboratory Animal Science,University of Veterinary Medicine Vienna,Vienna,Austria
Richard Moriggl
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria;Institute of Animal Breeding and Genetics,University of Veterinary Medicine Vienna,Vienna,Austria;Medical University of Vienna,Vienna,Austria
(Abstract release date: 05/19/16) EHA Library. Maurer B. 06/09/16; 132918; E1369
Ms. Barbara Maurer
Ms. Barbara Maurer
Contributions
Abstract
Abstract: E1369

Type: Eposter Presentation

Background
STAT5 transcription factors are essential regulators of differentiation, survival and proliferation during hematopoiesis. Hyperactive STAT5 signaling requires enhanced tyrosine phosphorylation (pYSTAT5), which is frequently found in hematopoietic cancers and is associated with negative prognosis. Importantly, recurrent gain-of-function STAT5 variants have been reported in Peripheral T Cell Lymphoma (PTCL) patients, who suffer from aggressive diseases with no targeted therapy options. 

Aims
We aim to analyze STAT5-dosage dependent effects on hematopoiesis. Here, we investigated whether constitutive activation of STAT5 suffices to drive PTCL and whether inhibition of the JAK/STAT pathway offers a novel therapeutic opportunity in this disease. 

Methods
We used cS5F, a hyperactive point mutant of STAT5A (S710F), to generate mouse models expressing the transgene under the vav-promoter at low (vcS5lo) or high (vcS5hi) levels from hematopoietic stem cells (HSC) on. The phenotypes were characterized by regular blood sampling, flow cytometric analysis of hematopoietic cells and HE, anti-CD3e and -Ki67 stainings on organ sections. RNA-seq and gene-set enrichment analysis was done to confirm the PTCL-like disease of vcS5hi mice. We quantified STAT5 expression levels in PTCL patient tissues by immunohistochemistry and qPCR. Effects on viability and pYSTAT5 levels of murine and human PTCL cell lines after JAK-STAT5 signalling inhibitor treatment were determined. 

Results
High pYSTAT5 levels in vcS5hi mice led to an aggressive expansion of CD8+ T cells being lethal between 25 and 45 weeks of age. In contrast, vcS5lo mice developed only a mild expansion of CD8+ T cells with no effect on life expectancy. The vcS5hi PTCL-like disease was associated with lymphadenopathy, splenomegaly and T cell infiltrations into various organs. The CD8+ T cells were transplantable and expressed T cell activation markers. Furthermore, the number of active cycling HSCs increased. The expression profile determined by RNA-seq correlated closely with human PTCL forms. STAT5 expression and activation levels were found to be elevated in PTCL patients. Treatment with Ruxolitinib, Tofacitinib and a novel STAT5 SH2-domain inhibitor decreased murine and human PTCL cell line viability in response to pYSTAT5 decline. 

Conclusion
Our results obtained from mouse models and patients support the concept that enhanced STAT5 signaling drives PTCL and that STAT5 represents a target in these life-threatening malignancies. 

Session topic: E-poster

Keyword(s): CD8 T cells, Inhibitor, Peripheral T-cell lymphoma, STAT5
Abstract: E1369

Type: Eposter Presentation

Background
STAT5 transcription factors are essential regulators of differentiation, survival and proliferation during hematopoiesis. Hyperactive STAT5 signaling requires enhanced tyrosine phosphorylation (pYSTAT5), which is frequently found in hematopoietic cancers and is associated with negative prognosis. Importantly, recurrent gain-of-function STAT5 variants have been reported in Peripheral T Cell Lymphoma (PTCL) patients, who suffer from aggressive diseases with no targeted therapy options. 

Aims
We aim to analyze STAT5-dosage dependent effects on hematopoiesis. Here, we investigated whether constitutive activation of STAT5 suffices to drive PTCL and whether inhibition of the JAK/STAT pathway offers a novel therapeutic opportunity in this disease. 

Methods
We used cS5F, a hyperactive point mutant of STAT5A (S710F), to generate mouse models expressing the transgene under the vav-promoter at low (vcS5lo) or high (vcS5hi) levels from hematopoietic stem cells (HSC) on. The phenotypes were characterized by regular blood sampling, flow cytometric analysis of hematopoietic cells and HE, anti-CD3e and -Ki67 stainings on organ sections. RNA-seq and gene-set enrichment analysis was done to confirm the PTCL-like disease of vcS5hi mice. We quantified STAT5 expression levels in PTCL patient tissues by immunohistochemistry and qPCR. Effects on viability and pYSTAT5 levels of murine and human PTCL cell lines after JAK-STAT5 signalling inhibitor treatment were determined. 

Results
High pYSTAT5 levels in vcS5hi mice led to an aggressive expansion of CD8+ T cells being lethal between 25 and 45 weeks of age. In contrast, vcS5lo mice developed only a mild expansion of CD8+ T cells with no effect on life expectancy. The vcS5hi PTCL-like disease was associated with lymphadenopathy, splenomegaly and T cell infiltrations into various organs. The CD8+ T cells were transplantable and expressed T cell activation markers. Furthermore, the number of active cycling HSCs increased. The expression profile determined by RNA-seq correlated closely with human PTCL forms. STAT5 expression and activation levels were found to be elevated in PTCL patients. Treatment with Ruxolitinib, Tofacitinib and a novel STAT5 SH2-domain inhibitor decreased murine and human PTCL cell line viability in response to pYSTAT5 decline. 

Conclusion
Our results obtained from mouse models and patients support the concept that enhanced STAT5 signaling drives PTCL and that STAT5 represents a target in these life-threatening malignancies. 

Session topic: E-poster

Keyword(s): CD8 T cells, Inhibitor, Peripheral T-cell lymphoma, STAT5

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