Basic and translational research exploring hyperactivation of the JAK-STAT core cancer pathway in hematopoietic cells

Led by Dr. Richard Moriggl

The Moriggl group performs basic and translational cancer research with the main focus of understanding and targeting the JAK-STAT core cancer pathway. We explore the mechanisms of disease manifestation upon hyperactivation or loss of JAK kinases and STAT3/5A/5B transcription factors. Key questions involve translation to address patient needs as we explore new targeting concepts and options. The Moriggl lab models human diseases using transgenic mouse strains and human recurrent somatic mutations identified based on cancer genome landscape studies. Established primary patient-derived cellular systems also help us to investigate neoplastic T cell development and therapeutic targeting options in peripheral T cell leukemia/lymphomas (PTCL), as well as acute myeloid leukemia (AML) or myeloproliferative diseases (MPN). Through close collaborative work, we also dissect mechanisms of transformation in solid tumors including carcinomas, sarcoma or melanoma, as well as perform research into infectious disease or chronic inflammation due to the importance of these processes in cancer onset and progression. The Moriggl lab also works on the understanding of gene regulatory changes and chromatin landscape remodelling upon hyperactivation or loss of JAK-STAT3/5 in cancer. We pursue the following major projects in the lab:

Chromatin remodeling through oncogenic STAT5 in PTCL

Increased STAT5 levels and activity are found in a variety of tumours, including T cell malignancies such as PTCL. Somatic mutations are frequently found in members of the JAK-STAT pathway in PTCL, including the aggressive gain-of-function mutation STAT5BN642H. STAT5 was shown to interact with and regulate, as well as be regulated by epigenetic modifiers. For example, STAT5 regulates DNA methylation via interactions with TET1/2 (leading to DNA hypomethylation) and it can directly induce DNMT1/3A target gene expression. However, it remains unclear how hyperactivation of the JAK-STAT pathway alters chromatin landscapes in favour of a malignant phenotype in PTCL. Moreover, STAT5 interacts with cell type-specific co-activators or co-repressors and these are also not yet identified in PTCL. Notably, drugs targeting chromatin remodelers (e.g., HDAC inhibitors) are showing promising efficacy in PTCL patients, highlighting the importance of chromatin landscape and transcriptional profiles in these diseases.


Regulation of open and closed chromatin by STAT5 and epigenetic modifiers. Figure adapted from Wingelhofer et al, 2018, Leukemia.

As a part of an FWF-funded Special Research Program (SFB F61), we are currently employing our novel cellular and murine PTCL model systems to investigate the effects of gain-of-function JAK-STAT mutations on chromatin remodelling and genomic landscape. Using state-of-the-art next-generation sequencing technologies, we are exploring STAT5 oligomer formation, chromatin looping structures, transcriptional profiles and chromatin accessibility in the context of PTCL. This knowledge will allow us to understand the epigenetic function of STAT5 in T cell lymphoma or other hematopoietic malignancies to form a basis for the development of personalized therapies in the future. We are also exploring how STAT5B hyperactivation can influence T cell biology and thymic development, and how this also relates to disease settings in T cell neoplasms.

Exploring metabolic networks for targeting therapies in T cell prolymphocytic leukemia

T cell prolymphocytic leukemia (T-PLL) is the most frequent mature T cell leukemia. Its chemotherapy resistance translates into an average patient survival of less than 20 months. There are no approved drugs for T-PLL and numerous exploratory or comparative trials to test novel therapies are not feasible due to the rare nature of the disease. Gene-regulatory, particularly epigenetic changes and metabolic cellular states, both also known to influence treatment responses in cancer, have not been examined in T-PLL. Overall, it is unclear how drug activity patterns relate to T-PLL’s molecular landscape. As a part of an ERA NET-funded consortia, we are exploring metabolic profiles in a cohort of T-PLL patient samples and matched healthy controls, using mass-spectrometry based untargeted metabolomics. This approach allows us to select specific analytes for further validation in T-PLL mouse models, as well as quantitative profiling of drug-induced phenotypic changes in T-PLL cells, using a selection of targeted compounds. Ultimately, this research aims to identify new molecular biomarkers and vulnerabilities in T-PLL and to develop novel targeted therapies.

Cancer research in companion and endangered animals

The Moriggl group also performs research to understand the underlying causes of cancers occuring in animal species. The Tasmanian devil is the largest existing marsupial carnivore that is found only on the island of Tasmania, Australia. The wild devil population has dropped by 80% as a result of two similar yet genetically distinct infectious cancers, referred to as devil facial tumor disease 1 and 2 (DFT1/2). These tumors are of schwannoma origin, similar to other sarcomas found in humans. However, they are capable of being transmitted from one individual to another.  We have discovered, together with the laboratory of Dr. Bergthaler from the CeMM (Vienna, Austria), that oncogenic ERBB-STAT3 signaling is driving DFT1 disease. Oncogenic STAT3 scavenges interferon-induced STAT1 signaling, blocking efficient surface expression of MHC-class I molecules, thereby achieving immune cell escape. We are currently engaged in international collaborations to explore DFT2 disease, especially with respect to targeting options. In other collaborative efforts, we work together with the laboratory of Dr. Kieslinger and Prof. Burgener at the Vetmeduni to research cancers frequently found in companion animals, including γδ T cell lymphoma in cats and osteosarcoma in dogs.

Targeting JAK kinases and STAT3/5-regulated transcription in myeloid and T cell neoplasms

In collaboration with the group of Prof. Patrick Gunning at the University of Toronto, we have previously reported a selective and specific STAT5 SH2-domain-targeting drug, AC-4-130. It was found to block MPN and AML cell growth and it also displays activity against PTCL. Developing on these findings, newer more potent generations of STAT5 inhibitors are currently being explored in a biotech collaboration. We have also started to explore targeting of gain-of-function variants of STAT3 as well as JAK3 that are frequently found somatically mutated in hematopoietic cancers. As a part of an FWF-funded Special Research Program (SFB F47), we are testing and characterizing new selective inhibitors that can block the oncogenic functions of the JAK-STAT pathway, with a main focus on STAT5 inhibitors. We are also exploring the efficacy of blocking JAK, STAT3 or STAT5 signaling in other diseases with complex genetic aberrations, such as cutaneous T cell lymphoma (CTCL) and T-PLL.

Model of STAT5 inhibitor AC-4-130 binding the STAT5 SH2 domain, as well as its efficacy in an in vivo AML mouse model and on patient samples. Figure adapted from Wingelhofer et al, 2018, Leukemia.

Biography

Principal Investigator,

Richard Moriggl, PhD

Professor for Functional Cancer Genomics

E-Mail | ORCID

Dr. Moriggl did his undergraduate study in Germany and France. He studied biotechnology in Germany and finished his PhD in 1997, working on cytokine signaling with Dr. Groner at the Friedrich Miescher Institute in Basel, Switzerland and at the Institute of Experimental Cancer Research in Freiburg, Germany. After a 4 year postdoctoral fellowship with Dr. Ihle at the St. Jude Children’s Research Hospital in Memphis, USA, in the area of immunology, he joined Dr. Beug at the Institute for Molecular Pathology in Vienna for a second postdoc to work on leukemia and stress hormone receptor signalling for another 5 years. Dr. Moriggl served as the director of the Ludwig Boltzmann Institute for Cancer Research for 14 years, heading up to six research groups that all got tenure tracked with professorships and integrated into medical research performing universities in Austria. His current appointment with the University of Veterinary Medicine involves the steering of the Unit for Functional Cancer Genomics with two subgroups headed by Dr. Heidi Neubauer and Dr. Anna Orlova, all integrated within the Institute of Animal Breeding and Genetics headed by Dr. Mathias Müller. The Moriggl group has largely third-party grant funded employees and runs researchers organized in smaller teams in a nice and stimulating scientific atmosphere, further embedded with many national and international collaboration partners.

Top Publications

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease. Kosack, L.*,Wingelhofer, B.*, Popa, A.*, Orlova, A.*, Agerer, B., Vilagos, B., Majek, P., Parapatics, K., Lercher, A., Ringler, A., Klughammer, J., Smyth, M., Khamina, K., Baazim, H., de Araujo, E.D., Rosa, D.A., Park, J., Tin, G., Ahmar, S., Gunning, P.T., Bock, C., Siddle, H.V., Woods, G.M., Kubicek, S., Murchison, E.P., Bennett, K.L., Moriggl, R.# & Bergthaler, A#. (2019) Cancer Cell, doi: 10.1016/j.ccell.2018.11.018. *equal contribution; #equal correspondence

STAT5BN642H is a driver mutation for T-cell neoplasia. Pham, H.T.T., Maurer, B., Prchal-Murphy, M., Grausenburger, R., Grundschober, E., Javaheri, T., Nivarthi, H., Boersma, A., Kolbe, T., Elabd, M., Halbritter, F., Pencik, J., Kazemi, Z., Grebien, F., Hengschläger, M., Kenner, L., Kubicek, S., Farlik, M., Bock, C., Valent, P., Müller, M., Rülicke, T., Sexl, V. & Moriggl, R. (2018) Journal of Clinical Investigation, doi: 10.1172/JCI94509

O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies. Freund, P., Kerenyi, M.A., Hager, M., Wagner, T., Wingelhofer, B., Pham, H.T., Elabd, M., Han, X., Valent, P., Gouilleux, F., Sexl, V., Krämer, O.H., Groner, B. & Moriggl, R. (2017) Leukemia, doi: 10.1038/leu.2017.4

Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Wingelhofer, B., Maurer, B., Heyes, E.C., Cumaraswamy, A.C., Berger-Becvar, A., Araujo, E.D., Orlova, A., Freund, P., Ruge, F., Jisung, P., Tin, G., Ahmar, S., Lardeau, C.H., Sadovnik, I., Bajusz, D., Keserü, G.M., Grebien, F., Kubicek, S., Valent, P. Gunning, P. & Moriggl, R. (2018) Leukemia, doi: 10.1038/s41375-017-0005-9

Adipocyte glucocorticoid receptor deficiency attenuates aging- or HFD-induced obesity and impairs the feeding-fasting transition. Müller, K.M., Hartmann, K., Kaltenecker, D., Vettorazzi, S., Bauer, M., Mauser, L., Amann, S., Jall, S., Fischer, K., Esterbauer, H., Müller, T.D., Magnes, C., Haybaeck, J., Scherer, J., Bordag, N., Tuckermann, J.P. & Moriggl, R. (2016) Diabetes, doi: 10.2337/db16-038

Memberships

  • American Association for Cancer Research (AACR)
  • International Society for Interferon and Cytokine Research (ISICR)

Associate Editor of Cytokine.

Group Members

Daniel Pölöske

PhD Student

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Helena Sorger

PhD Student

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Katrin Spirk

PhD Student

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Tobias Suske

PhD Student

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Christina Maria Wagner

PhD Student

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Marta Surbek

Master Student

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Stephanie Höbart

Lab Technician

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Garazi Monzo Contreras

Lab Technician

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Safia Zahma

Histology Technician

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Funding

FWF-Funded Special Research Programs (SFB)

FWF Der Wissenschaftsfonds

SFB F61: Monarchies and Hierarchies in Shaping Chromatin Landscapes

JakStat Monarchies

SFB F47: Myeloproliferative Neoplasms

Special Research Program – SFB F47

ERANET TRANSCAN-2 EU-Funded Project

The project “ERANET-PLL – Implementation of (epi)genetic and metabolic networks in the targeting of T cell prolymphocytic leukemia” was funded within the European ERANET TRANSCAN-2 initiative (Horizon 2020).

The consortium consists of five research groups from Vienna (Richard Moriggl, Philipp Staber), Cologne (Marco Herling), Lyon (Emmanuel Bachy) and Dresden (Ingo Roeder). The consortium, led by Marco Herling, received €1,500,000 in funding, of which €304,720 was allocated to the group in Vienna.

ERANET-PLL

Cancer research grant: Liechtenstein donation

2008-2019, International donation for melanoma research, cancer metabolism and colorectal cancer research.