Friday May 12th 2023, 11:00 am
Medical Research Center Kantonsspital St. Gallen & Cardioimmunology Universitätsspital Zürich CH (https://www.kssg.ch/prof-dr-burkhard-ludewig; https://www.usz.ch/en/clinic/cardiology/research/center-for-translational-and-experimental-cardiology-ctec/cardioimmunology/)
Title: Lymphoid organ fibroblasts
Host: Mathias Müller
Location: Vetmeduni Vienna Bldg NA, Room 07 B00
The SFB members Anna Orlova and Richard Moriggl are co-founders of the pharmaceutical start-up RIANA Therapeutics spun out of Vetmeduni Vienna in February 2023. RIANA Therapeutics focuses on developing novel anti-cancer treatments with hope to improve life of cancer patients.
For further information see https://www.vetmeduni.ac.at/en/universitaet/infoservice/presseinformationen/presseinformationen-2023/riana-viennese-start-up-develops-novel-precise-anti-cancer-drugs
The SFB Jak-Stat subproject leader Veronika Sexl took the lead of the University of Innsbruck (https://www.uibk.ac.at/en/) in March 2023. Veronika was appointed head of the rectorate in an international selection process for a period of four years. The SFB members congratulate Veronika to this highly responsible and prestigious position. We will miss Veronika’s scientific excellence and spirit in our team and wish her a successful and fruitful time in Innsbruck.
Richard Moriggl – a long-term member of the SFB – will take over the leadership of the subproject ‘Partners in Crime: STAT3 and CDK6 Control Transformation in Hematopoietic Cells’. We highly appreciate the commitment of Richard and look forward to exciting interactions.
Interferons (IFNs) activate cell-intrinsic defence mechanisms to fight infections. The innate immune response to infections overlaps and cooperates with cellular stress signalling governed by the mitogen-activated protein kinase (MAPK) p38. Laura Boccuni in the group of Thomas Decker unravelled the molecular mechanism how macrophages merge the IFN JAK-STAT and the stress p38 MAPK pathways to enhance the beneficial but also the detrimental effects of the innate and inflammatory responses. With the exception of one, all SFB groups contributed to this SFB-financed publication.
Published in Science Signaling
Laura Boccuni, Elke Podgorschek, Moritz Schmiedeberg, Ekaterini Platanitis, Peter Traxler, Philipp Fischer, Alessia Schirripa, Philipp Novoszel, Angel R. Nebreda, J. Simon C. Arthur, Nikolaus Fortelny, Matthias Farlik, Veronika Sexl, Christoph Bock, Maria Sibilia, Pavel Kovarik, Mathias Müller, Thomas Decker
Stress signaling boosts interferon-induced gene transcription in macrophages
https://doi.org/10.1126/scisignal.abq5389
See also for RELATED FOCUS: Rewiring the logic board of IFN signaling, by John D. MacMicking John D. MacMicking
https://doi.org/10.1126/scisignal.adf0778
The JAK-STAT signaling pioneers James E Darnell, John J O‘Shea and George R Stark and former or current co-workers in their labs co-author a comprehensive review on the current knowledge on the cellular and systemic activities of JAKs and STATs and possibilities of their therapeutic targeting in disease settings (see https://doi.org/10.1016/j.cell.2022.09.023).
The Viennese JAK-STAT community congratulates this fascinating pathway to its 30ies anniversary!
Tuesday November 15th 2022, 13.30
Clemens Schmitt
Kepler Universitätsklinikum / Johannes Kepler Universität Linz
Hämatologie und Internistische Onkologie (https://www.kepleruniklinikum.at/kliniken-einrichtungen/innere-medizin-3-haematologie-und-internistische-onkologie/team).
Title: Not just arrested – senescence-associated plasticity in cancer
Host: Veronika Sexl
Location: Vetmeduni Vienna Bldg NA, Room 07 B00 & Hybrid Blackboard Collaborate (https://eu.bbcollab.com/guest/eb6707f5a10e49b6b89f9d48d07a5cc5)
Wednesday June 8th 2022, 10 am
Matthias Ernst
Director, ONJCRI
Head Cancer and Inflammation Program and Laborartory
Head School of Cancer Medicine, La Trobe University (https://www.onjcri.org.au/about-us/matthias-ernst/).
Title: Targeting IL-11 to prevent oncogenic STAT3 signaling and Src kinase as regulator of myeloid cell proliferation
Host: Richard Moriggl
Location: Vetmeduni Vienna Bldg NA, Room 07 B00 & Hybrid Blackboard Collaborate (https://eu.bbcollab.com/guest/9ebec0a0bcf448e2a1dec957827b18ca)
Wednesday May 11th 2022, 10 am
Werner Held
Faculty of Biology and Medicine, Department of Fundamental Oncology, University of Lausanne, CH (https://applicationspub.unil.ch/interpub/noauth/php/Un/UnPers.php?PerNum=27453&LanCode=8).
Title: Stemness, exhaustion and reinvigoration of CD8+ T cells
Host: Mathias Müller
Location: Zoom
Innate immunity to viral infection is achieved by a group of polypeptide mediators, the interferons (IFN). By binding to cell surface receptors they initiate signal transduction via Janus kinases (JAK) that the STATs target, a group of transcription factors. STATs combine to form a transcription factor, ISGF3, that activates transcription of a large number of IFN-induced genes (ISG) encoding antiviral proteins and establishing an antiviral state.
We show that the transcription of antiviral genes includes important changes of chromatin structure (see below). First, ISGF3 binds to the control region of ISG to induce a rearrangement of nucleosomes that creates maximal accessibility of the promoter (below middle panel). Second, ISG that are arranged in chromosomal clusters change their chromatin loop structure to increase the interaction of regulatory elements (below right panel). The molecular model emerging from the study posits that interaction in the 3-dimensional space creates regulatory hubs with the ability to influence the expression of several clustered genes simultaneously. This may help to both coordinate, accelerate and strengthen the establishment of the antiviral state.
IFN stimulus alters the 3-dimensional chromatin architecture at antiviral gene clusters
Published in iScience
Ekaterini Platanitis, Sthephan Gruener, Aarathy Ravi Sundar Jose Geetha, Laura Boccuni, Alexander Vogt, Maria Novatchkova, Andreas Sommer, Iros Barozzi, Mathias Müller, Thomas Decker
Interferons reshape the 3D conformation and accessibility of macrophage chromatin
Our work builds on a previously published paper (https://doi.org/10.1038/leu.2016.277) describing germ-line TYK2 gain-of-function (GOF) mutations identified in childhood leukemia. In close collaboration with the Dutch pediatric oncologists we studied the oncogenic and druggable properties of the two activating mutations of this JAK family member tyrosine kinase. We demonstrate the transformation capacity of the potent TYK2P760L mutation in various hematopoietic cell systems and its tumorigenic potential upon transplantation into mouse models. The highly selective TYK2 inhibitor deucravacitinib blocked GOF TYK2 activity. A screen for kinase pathways co-operating with oncogenic TYK2 identified the PI3K/AKT/mTOR and CDK4/6 pathways as top hits. Combinatorial treatment of the TYK2inib with blockers of these pathways turned out to be more efficacious than single treatments and could be successfully translated to PDX cells derived from the TYK2P760L mutation carrying patient. The original work with contributions from the SFB members Birgit Strobl, Veronika Sexl, Richard Moriggl and Mathias Müller establishes novel treatment options for acute leukemia in patients harboring GOF TYK2 mutations and has not been submitted to publication elsewhere.
Published in Haematologica
Katharina Wöss, Sabine Macho-Maschler, Dorette S. Van Ingen Schenau, Miriam Butler, Caroline Lassnig, Daniel Valcanover, Andrea Poelzl, Katrin Meissl, Barbara Maurer, Tania Brandstoetter, Claus Vogl, Anna Koren, Stefan Kubicek, Anna Orlova, Richard Moriggl, Birgit Strobl, Veronika Sexl, Frank N Van Leeuwen, Roland P Kuiper, Mathias Müller
Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade
