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

Two publications from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna were awarded prizes. The article "STAT5 is a key regulator in NK cells and acts as molecular switch from tumor surveillance to tumor promotion", published in Cancer Discovery, received the research award from the City of Vienna Fund for innovative cancer research. The renowned Theodor Billroth Prize of the Vienna Medical Association was awarded to the publication "Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1 / 2 inhibitor therapy", published in Blood.

The City of Vienna Fund for Innovative Interdisciplinary Cancer Research is an initiative to support science and research in Vienna and to strengthen its importance in the public consciousness. This year's research funding award goes to a publication by first author Dagmar Gotthardt and last author Veronika Sexl from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna. The research group showed for the first time that natural killer cells produce a factor (VEGF-A; Vascular Endothelial Growth Factor A) that can promote tumour growth. This study also defines STAT5 as a master regulator of NK-cell proliferation and lytic functions. Link to the publication can be found here.

The Theodor Billroth Prize of the Vienna Medical Association was awarded to another study led by Veronika Sexl, including first authors Edit Porpaczy (MedUni Vienna), Sabrina Tripolt and Andrea Hölbl-Kovacic (Vetmeduni Vienna). The results of this study show a risk for patients with the rare bone marrow disease myelofibrosis when treated with a JAK1/2 inhibitor, which is commonly used as a standard drug. Founded by the Vienna Chamber of Physicians, the Theodor Billroth Prize supports young academics and scientific activities. The Prize was awarded on December 17th 2018 in Vienna. Link to the publication can be found here.

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

The best scientific posters at the Vetmeduni Vienna and the winners of the new VetIdeas Poster Challenge were announced as part of the 'That's Vet' show. The Poster Award was decided in two categories by a jury of science journalists and also by the University Council. The winners of the VetIdeas Poster Challenge were determined in advance by a jury decision.

After a one-year hiatus, Vetmeduni Vienna received another poster award in the 2018 edition of these prizes. All posters from 2017 and 2018 were eligible to participate. The best posters were again determined based on the nominations of science journalists and this year also with the support of the new University Council. At the same time, a new competition format was launched this year, the VetIdeas Poster Challenge, supported by the “tecnet equity” and “Accent Gründerservice”. Individual researchers or research teams were able to present ideas and concepts that could be implemented as products or intellectual propriety. In two workshops, the participants also learned how to present their work in a poster format and in a pitch. The workshop ended with the presentation of the poster and a pitch in front of a jury.

the Aegean Conferences 4th International Conference on Cytokines in Cancer meeting website for further info.

SFB-associated PhD students receive prizes in the Annual Poster Awards of Vetmeduni Vienna 2018

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

The Austrian Pharmacological Society has awarded the renowned Heribert Konzett Prize 2018 to Andrea Hölbl-Kovacic from the Institute of Pharmacology and Toxicology (in Veronika Sexl’s group). The award recognizes outstanding achievements in experimental and clinical pharmacology. This is the first time this prize is awarded to a member of the Vetmeduni Vienna. Andrea Hölbl-Kovacic convinced the selection with her excellent publication performance on the STAT5 protein and its role in the development of acute lymphoblastic leukemia.

Named after the renowned Austrian physician, pharmacologist and pioneer in the development of asthma drugs, the Heribert Konzett Prize is a high honour from the Austrian Pharmacological Society (APHAR). It is awarded annually to young scientists under 40 from the experimental field and clinical pharmacology, who have made outstanding achievements in this research field through independent, outstanding achievements, such as multiple publications in renowned specialist journals and third-party fundraising. On September 28, 2018, APHAR officially awarded the prize at a symposium in Graz, and for the first time to an employee of Vetmeduni Vienna. For her publications about STAT5’s role in leukemia, Andrea Hölbl-Kovacic previously received the Hans Horst Meyer Award from APHAR and the Funding Award from the City of Vienna Fund.

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