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

An international research team led by researchers from Vetmeduni Vienna have made an important discovery that could lead to a better understanding of lymphocytic leukemia. They identified the STAT5B protein as crucial for the development of the disease. The findings represent a possible therapeutic approach involving new, precision medicine strategies.

The BCR/ABL fusion gene, which does not occur among healthy people, has been shown to be a causative agent in the pathogenesis of B-cell acute lymphocytic leukemia (ALL). This gene leads to transformation of white blood cells, which can proliferate out of control. Earlier studies by the research group of Veronika Sexl at Vetmeduni Vienna showed that the STAT5 transcription factor was essential for the development of BCR/ABL-induced leukemia. Surprisingly, mutations in StatB, but not StatA, have been frequently described in hematopoietic tumors; therefore, the authors of this new study used BCR/ABL as a model system to disentangle the contribution of STAT5A or STAT5B for leukemogenesis. They found that the absence of STAT5A led to a decrease in cell survival and the formation of colonies of malignant cancer cells; the effects were even more drastic in the absence of STAT5B. In the mouse model, loss of STAT5B increased interferon response and suppressed transformation. The opposite scenario was true in patients with overactive STAT5B: the interferon response against tumour growth was suppressed and transformation was enhanced. According to the researchers, this may be of direct clinical relevance for patients, as a better understanding of the complex role of STAT5B could enable the development of precision medicine strategies to treat BCR/ABL ALL.

Published in Leukemia

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

Doi: https://doi.org/10.1038/s41375-018-0369-5

Facial tumours of Tasmanian devils belong to rare cases of transmissible cancers. More than 90% of the population of devils is extinct due to two distinct Schwannoma cell lines that spread among the species. They are of great interest for biomedical research, as they allow the study of fundamental properties of cancer cells and how they escape the host´s immune system. Using cutting-edge technologies, scientists of the group of Andreas Bergthaler at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and members of the groups of Richard Moriggl and Christoph Bock, both SFB JakStat Monarchies at the Vienna University of Veterinary Medicine together with international collaborators identified the ERBB receptor-STAT3 axis as key molecular mechanisms allowing for the transmissibility of the tumour cells. Importantly, the consortium showed that the inhibition of ERBB receptors with a selective tyrosine kinase inhibitor or pharmacologic intervention of STAT3 could selectively kill the transmissible cancer cells upregulating MHC class I allowing for immune cell recognition. This could play an important role for the treatment and understanding of the disease to rescue the Tasmanian devil in the isolated island from extinction.

Publication in Cancer Cell:

Lindsay Kosack, Bettina Wingelhofer, Alexandra Popa, Anna Orlova, Benedikt Agerer, Bojan Vilagos, Peter Majek, Katja Parapatics, Alexander Lercher, Anna Ringler, Johanna Klughammer, Mark Smyth, Kseniya Khamina, Hatoon Baazim, Elvin D. de Araujo, David A. Rosa, Jisung Park, Gary Tin, Siawash Ahmar, Patrick T. Gunning, Christoph Bock, Hannah V. Siddle, Gregory M. Woods, Stefan Kubicek, Elisabeth P. Murchison, Keiryn L. Bennett, Richard Moriggl and Andreas Bergthaler

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease (2019) DOI:https://doi.org/10.1016/j.ccell.2018.11.018

See also “The Deadly Bite of STAT3” mini review Cancer Cell by Hagen Schwenzer and Ariberto Fassati: DOI:https://doi.org/10.1016/j.ccell.2018.12.004

Facial tumours of Tasmanian Devils are among the extremely rare cases of transmissible cancer and threaten the survival of this species. They are extremely interesting for medical research because they can be used to unravel new cancer molecular mechanisms and their interplay with the immune system. Scientists at the Center for Molecular Medicine (CeMM), the Vetmeduni Vienna and the MedUni Vienna have succeeded in using modern analysis methods to elucidate key molecular mechanisms that are crucial for the transferability of these cancer cells.

Tumours can usually only proliferate in the organism from which they originated. This is due to a large number of molecular security mechanisms with which the immune system repels and destroys foreign tissue. An exception to this is the Tasmanian Devil, the largest living carnivorous marsupial in the world: a deadly facial tumour has been spreading at a rapid pace for over two decades in this species.

How these cells escape the immune system of its recipient has long been a mystery. Now, the groups of Andreas Bergthaler (CeMM) and Richard Moriggl, head of the Ludwig Boltzmann Institute for Cancer Research and Professor of Functional Cancer Genomics at the Vetmeduni and MedUni Vienna,

found that certain receptor molecules on the surface of the cancer cells, ERBB receptors, have unusually high activity. The activation of these receptors influences the cell's epigenetic make-up via STAT3. As a result, the number of molecules that the immune system uses to recognize the cell is reduced, while cell division accelerates and factors for the metastasis of the tumour cells are increasingly produced. Furthermore, inhibiting the ERBB receptor with a specific drug can kill cancer cells in a targeted manner. This could play an important role in treating this communicable tumour before the Tasmanian Devil is completely eradicated. In addition, the basic biological principles of invasion and fixation in new tissues are of crucial importance, even in the case of non-communicable tumours, in particular cancer metastases. A better molecular understanding of these relatively exotic communicable tumours can provide important insights into the basic biological mechanisms of cancer.

Published in Cancer Cell

Lindsay Kosack, Bettina Wingelhofer, Alexandra Popa, Anna Orlova, Benedikt Agerer, Bojan Vilagos, Peter Majek, Katja Parapatics, Alexander Lercher, Anna Ringler, Johanna Klughammer, Mark Smyth, Kseniya Khamina, Hatoon Baazim, Elvin D. de Araujo, David A. Rosa, Jisung Park, Gary Tin, Siawash Ahmar, Patrick T. Gunning, Christoph Bock, Hannah V. Siddle, Gregory M. Woods, Stefan Kubicek, Elisabeth P. Murchison, Keiryn L. Bennett, Richard Moriggl and Andreas Bergthaler

Doi: https://doi.org/10.1016/j.ccell.2018.11.018

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway is critical in tuning immune responses and its dysregulation is tightly associated with cancer and immune disorders. Disruption of interleukin (IL)-15/STAT5 signaling pathway due to the loss of IL-15 receptor chains, JAK3 or STAT5 leads to immune deficiencies with natural killer (NK) cell abnormalities. JAK1, together with JAK3 transmits signals downstream of IL-15, but the exact contribution of JAK1 to NK cell biology remains to be elucidated. In this study we show that deletion of NK cell-intrinsic JAK1 leads to an almost complete loss of NK cells in the spleen, blood, and liver, proving a crucial role of JAK1 in peripheral NK cells. The absence of one allele of Jak1 suffices to drastically impair NK cell function whereas the deletion of JAK2 in NK cells has no impact on their survival or maturation. We thus propose that in contrast to currently used JAK1/JAK2 inhibitors, the use of JAK2-specific inhibitors would be advantageous for the cancer patients by leaving NK cells intact.

Publication in Frontiers in Immunology

Agnieszka Witalisz-Siepracka, Klara Klein, Daniela Prinz, Nicoletta Leidenfrost, Gernot Schabbauer, Alexander Dohnal and Veronika Sexl

Loss of JAK1 Drives Innate Immune Deficiency (2019), doi: 10.3389/fimmu.2018.03108

See also Video:  https://drive.google.com/open?id=1lUNFRP4aLRZxr4-9VQkKV30IwV2EppKh

STAT1 exists as two alternatively spliced isoforms, STAT1α and STAT1β; the latter lacks the C-terminal transactivation domain (TAD). Our previous study with gene-modified mice expressing only the STAT1β isoform (Stat1β/β) demonstrated that STAT1β is capable of inducing a subset of IFNγ-responsive genes but the reason for the gene-selectivity remained unclear. In this study we used primary macrophages form wild-type and Stat1β/β mice to characterize the role of the C-terminal TAD in the transactivation and cofactor recruitment to paradigmatic IFNγ-responsive genes. Our key discoveries are that the STAT1β isoform is differentially required for (i) the recruitment of the Mediator coactivator complex and the transition of poised RNA polymerase II (Pol II) into productive elongation, (ii) the association of the general transcription factors TFIIH and p-TEFb to promoter elements specifically at late time points after stimulation or (iii) the establishment of active histone marks and the recruitment of Pol II to the STAT1 and IRF1 co-regulated gene promoters.

Collectively, our results shed new light on the communication of STAT1 with the transcriptional machinery and provide mechanistic insights into isoform-specific transcriptional activities of STAT1.

Publication in Frontiers in Immunology

Matthias Parrini, Katrin Meissl, Mojoyinola Joanna Ola, Therese Lederer, Ana Puga, Sebastian Wienerroither, Pavel Kovarik, Thomas Decker, Mathias Müller  and Birgit Strobl

The C-Terminal Transactivation Domain of STAT1 Has a Gene-Specific Role in Transativation and Cofactor Recruitment (2018), doi: 10.3389/fimmu.2018.02879

RNA helicase DDX3X is important for many aspects of RNA metabolism and RNA translation. In addition, several publications have highlighted a role for DDX3X in immunity, as it contributes to the induction of type I IFNs. However, the in vivo relevance of DDX3X in cells of hematopoietic origin remains unexplored. Using mouse genetics, we demonstrate that DDX3X makes important contributions to innate immunity against pathogens beyond its role in IFN induction, by influencing hematopoiesis as well as the transcription of many antimicrobial genes. By comparison between cells from male or female animals we show that DDX3X functions are in part compensated by its Y-chromosomal homologue DDX3Y. This suggests that DDX3X may be one of the factors contributing to well-established differences of the male and female immune systems. 

Publication in PLoS Pathogens

Daniel Szappanos, Roland Tschismarov, Thomas Perlot, Sandra Westermayer, Katrin Fischer, Ekaterini Platanitis, Fabian Kallinger, Maria Novatchkova, Caroline Lassnig, Mathias Müller, Veronika Sexl, Keiryn L. Bennett, Michelle Foong-Sobis, Josef M. Penninger and Thomas Decker

The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity (2018), https://doi.org/10.1371/journal.ppat.1007397

Anaplastic Large Cell Lymphomas (ALCL) is a rare type of lymphoma comprising approximately 16 percent of all T cell lymphomas. The molecular analysis of human tumour samples to find new, personalised therapeutic targets and their validation in tumour models has become a attractive approach in cancer research, which can advance clinical management of cancer patients. This is even more important for rare tumours, like ALCL, in which researchers rely on a very small number of patients. New research led by the international ERIA consortium and with the participation of the SFB members Richard Moriggl, Mathias Müller, Birgit Strobl has now identified that all sub-types of ALCL rely on the same signalling pathway for survival.

TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in some anaplastic large cell lymphomas (ALCL). Here the authors show that TYK2 is highly expressed in all cases of human ALCL and it prevents apoptotic cell death in ALCL human cell lines by increasing the expression of Mcl1, a pro-survival member of the BCL2 family. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells. Therefore, TYK2 represents an attractive drug target due to its unique enzymatic domain and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL. This is an urging therapy that still needs to be developed to treat immunological disorders, such as rare lymphomas.

Publication in Leukemia
Nicole Prutsch, Elisabeth Gurnhofer, Tobias Suske, Huan Chang Liang, Michaela Schlederer, Simone Roos, Lawren C. Wu, Ingrid Simonitsch-Klupp, Andrea Alvarez-Hernandez, Christoph Kornauth, Dario A. Leone, Jasmin Svinka, Robert Eferl, Tanja Limberger, Astrid Aufinger, Nitesh Shirsath, Peter Wolf, Thomas Hielscher, Fritz Aberger, Johannes Schmoellerl, Dagmar Stoiber, Birgit Strobl, Ulrich Jäger, Philipp B. Staber, Florian Grebien, Richard Moriggl, Mathias Müller, Giorgio G. Inghirami, Takaomi Sanda, A. Thomas Look, Suzanne D. Turner, Lukas Kenner and Olaf Merkel

Doi: https://doi.org/10.1038/s41375-018-0239-1

Hematopoietic stem cells (HSCs) sustain blood and immune cells in the body and are therefore crucial for our survival. HSCs are at rest, but as soon as blood needs to be formed - like after blood loss or chemotherapy - they are quickly activated to compensate for this loss. After completing their mission, they must return a dormant state. A team of scientists, including Christoph Bock (CeMM) and Veronika Sexl (Vetmeduni Vienna) – lead by Manuela Baccarini (Max F. Perutz Laboratories (MFPL)) – has now shown how intracellular signal transmissions can maintain this delicate balance between activation and dormancy. 

The switch between HSC active and inactive states requires a precisely regulated balance. It was already known that HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less was known about the cell-intrinsic pathways that control HSC dormancy. In this study, the researchers were able to describe in detail the intracellular networks responsible for this balance. The authors show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis. Importantly, they show that the feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/mTORC1 activation and that the MEK1 phosphorylation returns activated HSCs to quiescence. Overall, these results suggest a new role for the MEK/ERK pathway in hematopoiesis and that MEK inhibitors currently used for cancer therapy may find additional utility in controlling HSC activation.

Publication in Cell Stem Cell

Christian Baumgartner, Stefanie Toifl, Matthias Farlik, Florian Halbritter, Ruth Scheicher, Irmgard Fischer, Veronika Sexl, Christoph Bock and Manuela Baccarini

Doi: https://doi.org/10.1016/j.stem.2018.05.003