Matthias Ernst

Tuesday Novemember 15th 2022, 13.0 am 

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)

 

Matthias Ernst

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)

 

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