The Award Committee of the International Cytokine and Interferon Society (ICIS) selected the SFB PhD student Tobias Suske from Richard Moriggl’s lab for a Milstein Abstract Award in the amount of $500 in recognition of his presentation at Cytokines 2020 Virtual Meeting held at 1 - 4 November (https://seattle.cytokinesociety.org). The talk entitled “The Activating STAT5BN642H Driver Mutation Disrupts T Cell Development Progressing to T Cell Neoplasia” was given in the session “Structure-Function and Systems Biology of Cytokine Actions”.
The SFB members Birgit Strobl, Mathias Müller and Richard Moriggl show in complex mouse models and human cells the pivotal role of TYK2 in the development of severe organ damage during endotoxemia. Mechanistically the TYK2-dependent pathology was driven by murine caspase-11 (CASP11) or the human homolog CASP5 activity and the subsequent release of IL-1ß and IL-18.
Published in Cell Death & Differentiation
Andrea Poelzl, Caroline Lassnig, Sabine Tangermann, Dominika Hromadová, Ursula Reichart, Riem Gawish, Kristina Mueller, Richard Moriggl, Andreas Linkermann, Martin Glösmann, Lukas Kenner, Mathias Mueller & Birgit Strobl
TYK2 licenses non-canonical inflammasome activation during endotoxemia
Using sophisticated genetically engineered mouse models the SFB members Birgit Strobl, Mathias Müller and Veronika Sexl further dissect the NK cell-intrinsic and -extrinsic requirements for STAT1a versus STAT1b in NK cell biology and tumor surveillance.
Published in Frontiers in Immunology
Kartin Meissl, Natalija Simonović, Lena Amenitsch, Agnieszka Witalisz-Siepracka, Klara Klein, Caroline Lassnig, Ana Puga, Claus Vogl, Andrea Poelzl, Markus Bosmann, Alexander Dohnal, Veronika Sexl, Mathias Müller & Birgit Strobl
STAT1 isoforms differentially regulate NK cell maturation and anti-tumour activity
Therapeutic targeting of STAT3 by monobodies
An international consortium headed by the Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences ETH Lausanne collaborated with Veronika Sexl group members and developed the first monobodies targeted against STAT3. Monobodies are synthetic binding proteins engineered to selectively bind intracellular proteins – also those lacking an enzymatic domain. High affinity STAT3 monobodies were identified in a combinatorial phage and yeast display library sorting screen. The authors show selective interference of the monobodies with cellular STAT3 activity. This is an attractive therapeutic option due to STAT3’s homology with other STAT proteins that complicates the development of selective inhibitors.
Published in Nature Communications
Grégory La Sala, Camille Michiels, Tim Kükenshöner, Tania Brandstoetter, Barbara Maurer, Akiko Koide, Kelvin Lau, Florence Pojer, Shohei Koide, Veronika Sexl, Laure Dumoutier & Oliver Hantschel
Selective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains
Nikolaus Fortelny and Christoph Bock of CeMM showed the usefulness of knowledge-primed neural networks (KPNNs) for the interpretation of single-cell RNA-seq data. They expect that the use of deep learning on biological networks will also be relevant in other areas of biomedicine analysing big data sets, including metabolomics, proteomics and cellular or cognitive networks.
Published in Genome Biology
Nikolaus Fortelny and Christoph Bock
Knowledge-primed neural networks enable biologically interpretable deep learning on single-cell sequencing data
Special Issue ‚Targeting STAT3 and STAT5 in Cancer’ with Guest Editors Richard Moriggl (Vienna, AT), Patrick Gunning (Toronto, CA) and György Miklós Keserü (Budapest, HU). The Editorial of this Special Issue of Cancers (Basel) is now published: https://www.mdpi.com/2072-6694/12/8/2002.
The Special Issue contains various contributions of SFB members and associate members: https://www.mdpi.com/journal/cancers/special_issues/STAT_cancers
The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.
Nature News and Views: https://www.nature.com/articles/d41586-020-01916-2
Acute myeloid leukemia (AML) is an aggressive form of blood cancer that affects children and adults. In cases with particularly poor prognosis, this cancer is triggered by oncogenic fusion proteins, the formation of which involves the Nucleoporin 98 (NUP98) gene. A study published in the journal Blood results from a collaborative effort, including the groups of Richard Moriggl and Veronika Sexl of the Vetmeduni Vienna, and introduces a new therapeutic approach to fight this disease.
Genetic rearrangements, in which the NUP98 gene is involved, are rare genetic events that occur repeatedly in AML patients and are associated with a particularly poor prognosis - especially if this process occurs in children and adolescents. In a cooperation that included the Institute of Biochemistry and the Institute of Pharmacology at the Vetmeduni Vienna, researchers have for the first time identified the genes that are activated directly by NUP98 fusion proteins.
The authors developed novel mouse models that mimic the rare blood cancer AML, which included NUP98-fusion proteins. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling they discovered that NUP98-fusion proteins directly regulate leukemia-associated gene expression programs. Among these is the CDK6 protein, for which molecular inhibitors were already approved for clinical usage to treat other types of cancer. The authors then showed that treatment with CDK6 inhibitors significantly improved the survival of the test animals. Further clinical studies are now required to confirm the effectiveness of targeted CDK6 inhibition in patients suffering from AML.
Johannes Schmöllerl, Inês Amorim Monteiro Barbosa, Thomas Eder, Tania Brandstoetter, Luisa Schmidt, Barbara Maurer, Selina Troester, Ha Thi Thanh Pham, Mohanty Sagarajit, Jessica Ebner, Gabriele Manhart, Ezgi Aslan, Stefan Terlecki-Zaniewicz, Christa Van der Veen, Gregor Hoermann, Nicolas Duployez, Arnaud Petit, Helene Lapillonne, Alexandre Puissant, Raphael Itzykson, Richard Moriggl, Michael Heuser, Roland Meisel, Peter Valent, Veronika Sexl, Johannes Zuber and Florian Grebien
The Science Fund FWF supports promising research projects with a total volume of 8.6 million euros, in collaboration with the Austrian Academy of Sciences (ÖAW). This is intended to promote the innovative and interdisciplinary collaboration of outstanding postdoc teams from Austrian universities. One of the approved "Zukunftskollegs" will be carried out by member of the Vetmeduni Vienna in the field of preclinical development of peptide therapeutics for the treatment of autoimmune and inflammatory diseases. The aim is to establish a platform for interdisciplinary drug development and to make drug candidates available for further clinical development.
The "PeptAIDes drug development" (Peptides for the treatment of Autoimmune and Inflammatory Diseases) is one of four approved projects and will be developed by Dagmar Gotthardt (from Veronika Sexl’s group) together with Roland Hellinger (MedUni Vienna), who is responsible for the coordination of the project, Tim Hendrikx (MedUni Vienna), Eva-Maria Zangerl-Plessl and Kirtikumar Jadhav (University of Vienna). “We are proud that one of our young scientists was selected in such an extremely competitive environment with such high demands” said Otto Doblhoff-Dier, Vice Rector for Research and International Relations at the Vetmeduni Vienna. The research platform "PeptAIDes" encompasses the entire range of the scientific disciplines involved in drug development. The aim of the project is to test peptides in preclinical studies for a future use in clinical trial stages.
New findings from researchers at the Department for Functional Cancer Genomics at the Vetmeduni Vienna, in cooperation with the Technical University of Denmark (DTU), provide insights into mechanisms of immune cells that could affect future therapies for human diseases. The study called “The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5“ includes the participation of member of Richard Moriggl’s group.
Our immune system contains specialized cells that act as the first answer against pathogens such as bacteria and viruses. These cells are called gamma-delta (γδ) T cells and are mainly found in organs such as the intestine, lungs, skin and lymph nodes. However, this specific T cells can also promote autoimmune and immune-related diseases such as psoriasis and multiple sclerosis. Understanding the basic biology of γδ T cells is essential in order to find ways to treat these diseases. In addition, by controlling the γδ T cells in a targeted manner, one could envision the use of these cells to fight infections and inflammations. This new study shows, for example, that STAT5 is necessary for the growth of certain types of γδ T cells during neonatal mouse life. Mice that do not express STAT5 do not produce these T cells and are resistant to multiple sclerosis. Furthermore, the authors describe a new type of γδ T cells that can only be found in the intestine. This new cell type has different functions than other types of γδ T cells and requires STAT5 for its growth. The results imply that the newly identified cell type is an important defence mechanism against intestinal infections shortly after birth. Therefore, manipulation of γδ T cells may help to strengthen immunity in early age.
Published in The Journal of Clinical Investigation
Darshana Kadekar, Rasmus Agerholm, John Rizk, Heidi A. Neubauer, Tobias Suske, Barbara Maurer, Monica Torrellas Viñals, Elena M. Comelli, Amel Taibi, Richard Moriggl, and Vasileios Bekiaris