Andreas Pichlmair,
Institute of Virology,
TU Munich

Title: Organization of intracellular defense mechanisms and disturbance by viruses

https://innatelab.virologie.med.tum.de/archives/458;

https://www.virologie.med.tum.de/forschung-tum/ag-pichlmair/

Andreas Pichlmair’s group is interested in understanding interactions between pathogenic viruses and their hosts on molecular and functional level, focusing on RNA-protein and protein-protein interactions.

 

As part of the 3rd International Conference on Cytokine Signaling in Cancer in Rhodes, Greece, the Travel Awards were again awarded this year. Two of the awards went to Sebastian Kollmann from the Institute of Pharmacology and Toxicology and Anna Orlova from the Department of Functional Cancer Genomics at Vetmeduni Vienna.

In the project "STAT5A and STAT5B in Hematopoietic and Leukemic Stem Cells - Between Death and Immortality", Sebastian Kollmann addresses the question of why mutations in lymphoma and leukemia patients are mainly found in STAT5B and hardly in the related protein STAT5A. It describes an important role for STAT5B in the self-renewal of hematopoietic and leukemic stem cells and thereby contributes with basic information to understand this question.

In the study “The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease”, Anna Orlova shows that the overactivation of ERBB receptors, and consequently also of STAT3, leads to the transferability of facial tumours among Tasmanian devils. The study also unravels that the cancer cells can be specifically targeted by drug inhibition of the ERBB receptor.

Tobias Suske is a PhD student in the group of Richard Moriggl at the Institute of Animal Breeding and Genetics, Vetmeduni Vienna. He was honored with the Young Investigator Award at the Annual Meeting of the OeGHO & AHOP in Linz AT for his excellent talk on “The gain-of-function STAT5BN642H mutation as a driver of T-cell lymphoma and leukemia”.

The Austrian Society for Haematology and Clinical Oncology (OeGHO, www.oegho.at) and the Working Group for Haematological and Oncological Nursing (AHOP, www.ahop.at) have been awarding outstanding research of young investigators since 2010. The award is € 1.000 and is donated by Janssen Cilag Pharma GmbH.


©OeGHO


©OeGHO

In a triple-effort between international research groups from the University of Veterinary Medicine Vienna, Harvard University and the University of Toronto, important new information was discovered about the protein STAT5B, which is mutated in patients with T-cell cancers. STAT5B, like all proteins, is made up of building blocks called amino acids. A single amino acid change in STAT5B makes it hyperactive and leads to T-cell cancer development. We have tackled the difficult task to visualize the structure and shape of STAT5B in order to facilitate the discovery of new drugs that specifically target the mutant cancer-causing form of the protein, whilst sparing the important normal-functioning STAT5B.

We have used a technique similar to medical X-rays to reveal for the first time the three-dimensional structures of normal and mutant STAT5B down to the atomic level. We also developed a new cancer mouse model driven by mutant STAT5B, which allows the study of one of the most aggressive T-cell cancers seen in patients. Importantly, the structural information and the disease model can now be used to test new drugs that target only the cancer-causing form of STAT5B, which will significantly reduce the side-effects and increase the effectiveness of the treatment.

Publication in Nature Communications

Elvin D. de Araujo*, Fettah Erdogan*, Heidi A. Neubauer*, Deniz Meneksedag-Erol, Pimyupa Manaswiyoungkul, Mohammad S. Eram, Hyuk-Soo Seo, Abdul K. Qadree, Johan Israelian, Anna Orlova, Tobias Suske, Ha T. T. Pham, Auke Boersma, Simone Tangermann, Lukas Kenner, Thomas Rülicke, Aiping Dong, Manimekalai Ravichandran, Peter J. Brown, Gerald F. Audette, Sarah Rauscher, Sirano Dhe-Paganon, Richard Moriggl and Patrick T. Gunning

*equal author contribution; corresponding authorship

Structural and functional consequences of the STAT5BN642H driver mutation (2019); Doi: https://doi.org/10.1038/s41467-019-10422-7

Tobias Suske, PhD student at the Institute for Animal Breeding and Genetics at Vetmeduni Vienna, was awarded at the Annual Meeting of the Austrian Society for Hematology and Medical Oncology (OeGHO) and the Working Group for Hematological and Oncological Nurses (AHOP) spring conference 2019 for his outstanding presentation “The gain-of-function STAT5BN642H mutation as a driver of T-cell lymphoma and leukemia”. With his work, he won the Young Investigator Award.

Tobias Suske from the Functional Cancer Genomics Department at the Institute of Animal Breeding and Genetics received one of the young talent awards. The Young Investigator Awards are endowed with 1000€ each and are awarded by Janssen Cilag Pharma GmbH. In his PhD project, Tobias Suske studied the STAT5BN642H mutation. This genetic change has been found frequently in recent years in patients with T-cell lymphomas and leukemias, who are usually extremely aggressive and difficult to treat. The research focuses on understanding the mutation at the molecular level in order to create therapeutic approaches for targeted active substances.

An international research team led by Veronika Sexl from Vetmeduni Vienna and supported by other members of SFB ‚JakStat Monarchies‘ have made an important discovery that could lead to a better understanding of lymphocytic leukemia: the STAT5B protein – but not the highly related STAT5A isoform – is crucial for disease development by suppressing interferon signals during leukemic transformation. Our findings will enable novel therapeutic approaches in precision medicine.

Publication in Leukemia:

Sebastian Kollmann, Eva Grundschober, Barbara Maurer, Wolfgang Warsch, Reinhard Grausenburger, Leo Edlinger, Jani Huuhtanen, Sabine Lagger, Lothar Hennighausen, Peter Valent, Thomas Decker, Birgit Strobl, Mathias Mueller, Satu Mustjoki, Andrea Hoelbl-Kovacic and Veronika Sexl

Twins with different personalities: STAT5B—but not STAT5A—has a key role in BCR/ABL-induced leukemia (2019), https://doi.org/10.1038/s41375-018-0369-5

Wilfried Ellmeier,
Division of Immunobiology,
Institute of Immunology, MedUni Vienna;
Coordinator of newly granted SFB F70 ‘HDACs as regulators of T cell-mediated immunity in health and disease’
(http://www.meduniwien.ac.at/HIT/)

Title: Histone deacetylases and the control of CD4+ T cell-mediated immunity

http://www.meduniwien.ac.at/immunologie/ellmeier

The long-term research interest of Wilfried Ellmeier’s group is to characterize molecular mechanisms that regulate the development and function of T lymphocytes. They aim to provide important and medical relevant insight into the regulation of T cell-mediated immunity.

 

We used conditional ablation of STAT1 in macrophages, monocytes and granulocytes of mice and showed that myeloid STAT1 protects from early murine cytomegalovirus replication and pathology in spleen. Unexpectedly, we found that myeloid STAT1 drives extramedullary haematopoiesis (EMH). STAT1 promotes EMH not only after virus infection but also upon sterile inflammation induced by CpG oligodeoxynucleotides. Using additional genetically engineered mice we analysed the impact of upstream signals known to activate STAT1 and observed that virus-induced EMH does not rely on type I or type II IFN signaling in myeloid cells or IL-27 signaling in all cell types. Our studies provide the first genetic evidence that STAT1-dependent signaling in myeloid cells restricts MCMV at early time points post infection and induces compensatory (stress-induced) haematopoiesis in the spleen.

Publication in Cell Reports

Riem Gawish*, Tanja Bulat*, Mario Biaggio*, Caroline Lassnig, Zsuzsanna Bago-Horvath, Sabine Macho-Maschler, Andrea Poelzl, Natalija Simonović, Michaela Prchal-Murphy, Rita Rom, Lena Amenitsch, Luca Ferrarese, Juliana Kornhoff, Therese Lederer, Jasmin Svinka, Robert Eferl, Markus Bosmann, Ulrich Kalinke, Dagmar Stoiber, Veronika Sexl, Astrid Krmpotić, Stipan Jonjić, Mathias Müller, and Birgit Strobl

*equal author contribution

Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1 (2019); Doi: https://doi.org/10.1016/j.celrep.2019.02.017

We used conditional ablation of TYK2 in mice and showed that TYK2 promotes NK cell activity in tumour surveillance and the defence against Listeria monocytogenes infection through cell-extrinsic and -intrinsic mechanisms. The key discoveries are as follows: NK cell-extrinsic TYK2 drives peripheral NK cell maturation, demethylation of the Ifng locus, activating receptor-induced IFNg production, cytotoxicity and anti-tumour activity; the NK cell defects observed in Tyk2-/- mice can be restored by recombinant IL-15/IL-15Rα treatment; NK cell-intrinsic TYK2 signalling mediates infection-induced IFNg production and acts protective during Listeria monocytogenes infection.

Collectively, our study disclosed TYK2 functions that remained unrecognized in mice with complete TYK2 deficiency. Our findings that cytotoxic defects of Tyk2-/- NK cells can be rescued by IL-15/IL-15Rα treatment suggest that unwanted effects of TYK2 inhibitors in tumour therapy may be overcome by boosting NK cell activity.

Publication in Journal of Immunology

Natalija Simonović * , Agnieszka Witalisz-Siepracka *, Katrin Meissl, Caroline Lassnig, Ursula Reichart,  Thomas Kolbe,  Matthias Farlik, Christoph Bock, Veronika Sexl, Mathias Müller, and Birgit Strobl

*equal author contribution

NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity (2019); Doi:

https://doi.org/10.4049/jimmunol.1701649

The symposium will be held at the Vetmeduni Vienna on January 31 and February 01, 2019. The symposium invited speakers from the Vienna Life Science community and from the Vetmeduni Vienna who work in basic and translational biomedical sciences to pave the road for new therapeutic concepts. Their research contributions serve as role models for students and early career scientists. We train students of the MSc program ‘Comparative Biomedicine’on our campus under the principle of “One Health – One Medicine”. The symposium is organized and supported by SFB F61 JakStat Monarchies.

Link to PDF of Program