JAK-STAT 30th Anniversary

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 […]

Katarzyna Sitnik wins Merit Award of CMV Conference

  https://www.cmv2022.org Abstract of Oral Presentation Pdgfra-positive fibroblasts are a major site of mouse cytomegalovirus latency in vivo. Latent cytomegalovirus (CMV) infections pertain to most of the human population, yet our understanding of the cell types that carry latent CMV in vivo remains limited. While endothelial cells and macrophages have been identified previously as sites […]

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

https://doi.org/10.1016/j.isci.2022.103840

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

https://doi.org/10.3324/haematol.2021.279848 

Vetmeduni Vienna, January 25th 2021:

Extension of “Monarchies and Hierarchies in Shaping Chromatin Landscapes” Special Research Programme funded by Austrian Science Fund FWF

https://www.vetmeduni.ac.at/en/infoservice/press-releases/presseinformationen-2021/extension-of-monarchies-and-hierarchies-in-shaping-chromatin-landscapes-special-research-programme/

 

Second funding period (2021-2025) for SFB F61 approved in the FWF Board meeting from 23rd to 25th of November 2020.

 

Summary of the Research Program

The STAT proteins are transcription factors with a central role in cell homeostasis, survival and differentiation. They are activated by the JAK kinases, including TYK2. Dysregulated STATs cause immune- or inflammation-related, metabolic and tumorigenic diseases but how STATs interact with chromatin is unknown. We have compiled a map of chromatin activity for all wildtype STATs, TYK2, oncogenic STAT5B and a kinase-inactive TYK2 mutant in primary immune cells and in structural cells under homeostatic, cytokine-induced and cell-transforming conditions and plan to use it to determine how JAK-STAT exerts its manifold effects.

The SFB groups hypothesise

  • STATs and TYK2 cause chromatin remodeling in non-hematopoietic cells, defining their identity and shaping the interface of immune cells and stromal cells in homeostasis and disease (Christoph Bock, Mathias Müller, Birgit Strobl with all other consortium members)
  • Homeostatic macrophages use STAT2/IRF9 to prime themselves for activation (Thomas Decker, Sylvia Knapp and Christoph Bock); signals from STAT1,3,5 drive the exit from and the return to homeostasis (Sylvia Knapp, Mathias Müller, Birgit Strobl, Thomas Decker and Christoph Bock)
  • STAT5A and STAT5B are not equivalent but drive distinct developmental programs in haematopoietic and leukaemic cells (Veronika Sexl, Heidi Neubauer and Christoph Bock)
  • The chromatin signatures of haematopoietic cancers are shaped by oncogenic STAT5, oncogenic STAT3 or a STAT3-CDK6 complex (Veronika Sexl, Heidi Neubauer and Christoph Bock)
  • TYK2 determines cell fate by regulating both transcriptional and post-transcriptional processes (Birgit Strobl, Mathias Müller and Christoph Bock with Thomas Decker).

 

Much of the current work on signal transduction in disease conditions (e.g. during infection, transformation or drug treatment) is based on an outdated understanding of the homeostatic healthy condition. By providing a fine-scale and cell-specific definition, our work will cause a comprehensive (re-)evaluation of the early stages of perturbations and the return to homeostasis. The approach is completely novel and will revolutionize our understanding of cellular memory and the progression/resolution of disease.

Press Release

In Q2 2021 a common seminar series of the FWF-funded Vienna Life Science Region research consortia of DocFund TissueHome (speakers Karl Kuchler & Birgit Strobl; https://tissuehome.meduniwien.ac.at), SFB HIT: HADCs – Immunomolulation – T cells (speaker Willfried Ellmeier; https://www-new.meduniwien.ac.at/HIT/) and the SFB JAK-STAT & Chromatin Landscapes (speakers Mathias Müller & Thomas Decker) will start. Please look out for the upcoming announcements.

Press Release

Joined forces of FWF SFB with DFG TRR:

the Viennese JAK-STAT consortium and the DFG funded Transregio (TRR) research consortium ‘Determinants and Dynamics of Elimination versus Persistence of Hepatitis Virus Infection’ (TRR179) coordinated by Ralf Bartenschlager (http://www.trr179.de/en/) initiated a collaboration with future researcher exchanges and lab visitations.

Press Release

Thomas Krausgruber receives the Karl Landsteiner Award for Immunological Basic Research of the Austrian Society for Allergology and Immunology (ÖGAI, www.oegai.org) handed over at the Virtual Congress Day December 4th 2020.

The Award Committee of the ÖGAI supported by international reviewers selected Thomas Krausgruber from Christoph Bock’s lab for his work and widely recognized publication in Nature entitled ‘Structural cells are key regulators of organ-specific immune responses’ (https://doi.org/10.1038/s41586-020-2424-4). which was supported by funding of the FWF for the SFB. The award in the amount of 4000€ is donated by the Karl Landsteiner & Eisler-Terramare Foundation – Memorial Private Foundation.

Vetmeduni Vienna, January 25th 2021:

Extension of “Monarchies and Hierarchies in Shaping Chromatin Landscapes” Special Research Programme funded by Austrian Science Fund FWF

https://www.vetmeduni.ac.at/en/infoservice/press-releases/presseinformationen-2021/extension-of-monarchies-and-hierarchies-in-shaping-chromatin-landscapes-special-research-programme/

 

Second funding period (2021-2025) for SFB F61 approved in the FWF Board meeting from 23rd to 25th of November 2020.

Summary of the Research Program

The STAT proteins are transcription factors with a central role in cell homeostasis, survival and differentiation. They are activated by the JAK kinases, including TYK2. Dysregulated STATs cause immune- or inflammation-related, metabolic and tumorigenic diseases but how STATs interact with chromatin is unknown. We have compiled a map of chromatin activity for all wildtype STATs, TYK2, oncogenic STAT5B and a kinase-inactive TYK2 mutant in primary immune cells and in structural cells under homeostatic, cytokine-induced and cell-transforming conditions and plan to use it to determine how JAK-STAT exerts its manifold effects.
The SFB groups hypothesise
• STATs and TYK2 cause chromatin remodeling in non-hematopoietic cells, defining their identity and shaping the interface of immune cells and stromal cells in homeostasis and disease (Christoph Bock, Mathias Müller, Birgit Strobl with all other consortium members)
• Homeostatic macrophages use STAT2/IRF9 to prime themselves for activation (Thomas Decker, Sylvia Knapp and Christoph Bock); signals from STAT1,3,5 drive the exit from and the return to homeostasis (Sylvia Knapp, Mathias Müller, Birgit Strobl, Thomas Decker and Christoph Bock)
• STAT5A and STAT5B are not equivalent but drive distinct developmental programs in haematopoietic and leukaemic cells (Veronika Sexl, Heidi Neubauer and Christoph Bock)
• The chromatin signatures of haematopoietic cancers are shaped by oncogenic STAT5, oncogenic STAT3 or a STAT3-CDK6 complex (Veronika Sexl, Heidi Neubauer and Christoph Bock)
• TYK2 determines cell fate by regulating both transcriptional and post-transcriptional processes (Birgit Strobl, Mathias Müller and Christoph Bock with Thomas Decker).

Much of the current work on signal transduction in disease conditions (e.g. during infection, transformation or drug treatment) is based on an outdated understanding of the homeostatic healthy condition. By providing a fine-scale and cell-specific definition, our work will cause a comprehensive (re-)evaluation of the early stages of perturbations and the return to homeostasis. The approach is completely novel and will revolutionize our understanding of cellular memory and the progression/resolution of disease.

Press Release

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”.