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

Doi: https://doi.org/10.1182/blood.2019003267

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

Doi:10.1172/JCI131241

Researchers from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in collaboration with the Vetmeduni Vienna (including members of Richard Moriggl’s group), MedUni Vienna, Hannover Medical School, St. Gallen Cantonal Hospital and Bio-Cancer Treatment International Ltd identified a key mechanism that explains how antiviral immune responses can reprogram liver metabolism. 

The liver is a crucial organ for the systemic metabolism in our body. In addition to the turnover of biomolecules and drug metabolism, the liver removes toxic substances from the organism. The liver is thus a central metabolic hub in a healthy organism, but is also a central organ in the immune defence against infections - previous studies have shown how immune cells improve the liver metabolism to fight pathogens or cancer. Based on this, the authors of the article now published in the journal Immunity examined these immune metabolic changes during viral infection of mice. In addition to the expected inflammatory changes, the authors identified strong changes in liver metabolism. They were able to show that many central metabolic pathways, including the urea cycle, are suppressed when an infection occurs. The antiviral cytokine type I interferon (IFN-I) was then identified as a regulator of the urea cycle - after removal of the receptor for IFN-I from the surface of hepatocytes, the metabolic changes were no longer observed. This was a surprising observation that shows that IFN-I influences important biological processes during an infection. The results shed a new light on how the body's immune system has developed to regulate liver metabolism so that it controls T cell responses while reducing collateral tissue damage during infection.

Published in Immunity

Alexander Lercher*, Anannya Bhattacharya*, Alexandra M. Popa, Michael Caldera, Moritz F. Schlapansky, Hatoon Baazim, Benedikt Agerer, Bettina Gürtl, Lindsay Kosack, Peter Májek, Julia S. Brunner, Dijana Vitko, Theresa Pinter, Jakob-Wendelin Genger, Anna Orlova, Natalia Pikor, Daniela Reil, Maria Ozsvár-Kozma, Ulrich Kalinke, Burkhard Ludewig, Richard Moriggl, Keiryn L Bennett, Jörg Menche, Paul N. Cheng, Gernot Schabbauer, Michael Trauner, Kristaps Klavins and Andreas Bergthaler (*shared first authors)

Doi: https://doi.org/10.1016/j.immuni.2019.10.014

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

Concept of a Dual Degrader, © Ingeborg Menzl

Acute lymphoblastic leukemia (ALL) is a rare cancer that affects mostly affects children. In the search for new therapeutic options, researchers at Vetmeduni Vienna have now discovered a new mechanism of disease development and proposed a completely new treatment - a pioneering work for future cancer therapies. The study has just been published in Nature Communications.

 

Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. The research team of Veronika Sexl at the Vetmeduni Vienna - in collaboration with the research team of Nathanael Gray from Harvard Medical School (USA) - focused on CDK8 in the search for new therapeutic routes for ALL. The reason for this is that tumorigenic cells are dependent on CDK8 function, while healthy cells are not. This opens up a therapeutic window by targeting CDK8: healthy cells are spared while cancer cells will be affected.

The research team was able to show that leukemia cells that lose CDK8 in leukemia mouse models significantly enhance disease latency and prevents disease maintenance. Furthermore, CDK8-depleted cancer cells are highly sensitive to mTOR inhibitors, a previously unknown connection. Thus, the authors have synthesized a small molecule (YKL-06-101) that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. This represents a new therapeutic line in drug development: a dual degrader drug is sufficient to break down a molecule - CDK8 - and at the same time enzymatically block a signalling pathway. They propose that by affecting both simultaneously a potential therapeutic strategy for the treatment of ALL patients might be developed.

Published 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

Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects small children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. While LCH can heal itself in some patients, other cases require intensive chemotherapy with long-term consequences for the children. The reasons for these differences are hardly known. In a new study published in the journal Cancer Discovery, researchers from St. Anna Children's Cancer Research Institute (CCRI) and the Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM) uncovered important insights into the cellular heterogeneity and molecular mechanisms of LCH.

Caroline Hutter, pediatric oncologist at St. Anna Children's Hospital, observed a remarkable heterogeneity between LCH cells when examining LCH lesions under the microscope. In order to investigate this diversity in detail, she assembled an interdisciplinary team of experimental and computer researchers from CCRI and CeMM, as well as physicians from St. Anna Children's Hospital and General Hospital in Vienna. Caroline Hutter's aim is to answer two fundamental questions: What are the mechanisms behind LCH and how can we improve the treatment of children affected by this disease?

LCH lesions were analysed in the laboratory of Christoph Bock (CeMM), by Florian Halbritter (now at CCRI) and Matthias Farlik (now at the MedUni Vienna), with sufficient resolution to identify the molecular patterns of individual cells in detail and to develop a comprehensive "map" of cellular heterogeneity in LCH. On this molecular map, the team identified several subtypes of LCH cells. Among them was a group of actively dividing cells that are believed to be the precursors of other LCH cells. The team deciphered the molecular signalling pathways that are active in different branches of this unexpected developmental hierarchy, highlighting an interplay of developmental, immunological and oncogenic mechanisms in LCH. In the future, these findings could help to better differentiate between severe and less severe cases of the disease and even open up new treatment options.

Published in Cancer Discovery
Florian Halbritter, Matthias Farlik, Raphaela Schwentner, Gunhild Jug, Nikolaus Fortelny,
Thomas Schnoller, Hanja Pisa, LindaChristina Schuster, Andrea Reinprecht, Thomas Czech,
Johannes Gojo, Wolfgang Holter, Milen Minkov, Wolfgang M Bauer, Ingrid Simonitsch Klupp, Christoph Bock and Caroline Hutter

Doi:10.1158/2159-8290.CD-19-0138

New insights into the development of an unusual childhood disease

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

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

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