Aside

Acute lymphoblastic leukemia (ALL) is a rare form of cancer that commonly affects children, mostly under the age of five years. In the search for new therapeutic options, researchers at Vetmeduni Vienna funded by the FWF SFB ‘JAK-STAT & Chromatin Landscapes’ have discovered cyclin-dependent kinase 8 (CDK8) as part of the disease process and have developed a novel drug treatment line that is pioneering for future cancer therapies.

Using leukemia mouse models, first author Ingeborg Menzl from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna and her colleagues demonstrated that CDK8-deficient leukemia cells show an increase in cell death. Notably, this function of CDK8 in ALL is independent of enzymatic activity, which means that conventional kinase inhibitors are ineffective. The search for CDK8 interaction partners revealed a previously unknown link to mTOR signaling in cancer cells.

Dual degrader – a therapy line with combined effect. In collaboration with the research team of Nathanael Gray from the Harvard Medical School, the researchers used a new generation of drugs that do not block enzymatic activity but induce the degradation of proteins (called PROTACs). Using a newly synthesized PROTAC mTOR signaling was blocked while simultaneously CDK8 was degraded. With this concept of a dual degrader, the researchers are pioneering for future cancer therapies.

Publication in Nature Communications

Ingeborg Menzl, Tinghu Zhang, Angelika Berger-Becvar, Reinhard Grausenburger, Gerwin Heller, Michaela Prchal-Murphy, Leo Edlinger, Vanessa M. Knab, Iris Z. Uras, Eva Grundschober, Karin Bauer, Mareike Roth, Anna Skucha, Yao Liu, John M. Hatcher, Yanke Liang, Nicholas P. Kwiatkowski, Daniela Fux, Andrea Hoelbl-Kovacic, Stefan Kubicek, Junia V. Melo, Peter Valent, Thomas Weichhart, Florian Grebien, Johannes Zuber, Nathanael S. Gray and Veronika Sexl;

Doi: https://doi.org/10.1038/s41467-019-12656-x

The interferons initiate a signaling process that causes the cell to activate the protein complex ISGF3 for driving antimicrobial gene expression. Scientists led by Thomas Decker at the Max Perutz Labs now found out that two of the three proteins forming this complex are permanently present at these genes, independently of the activating cascade caused by interferons. STAT2-IRF9 forms this ‘light’ version of ISGF3 and allows for homeostatic low expression of antimicrobial genes. Upon pathogen recognition interferons are produced and activate the complete version of ISGF3 composed of STAT1-STAT2-IRF9.  This trimeric ISGF3 switches to a full-fledged antimicrobial transcriptional program. The homeostatic presence of STAT2-IRF9 at antimicrobial genes governs cellular alertness and the rapid exchange to the interferon induced complete ISGF3 explains how the innate immune system activates in such a quick manner.

Publication in Nature Communications

Ekaterini Platanitis, Duygu Demiroz, Anja Schneller, Katrin Fischer, Christophe Capelle, Markus Hartl, Thomas Gossenreiter, Mathias Müller, Maria Novatchkova and Thomas Decker

A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription (2019);

Doi: https://doi.org/10.1038/s41467-019-10970-y

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

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