Team Zebisch

Research focus: Inflammation, autoimmunity and cancer

PI: Armin Zebisch

Focus: Myeloid leukemias are devastating hematologic cancers with a dismal prognosis in affected patients. Our research group aims to delineate the molecular basis of myeloid leukemia development and use this knowledge to design novel treatment approaches. We are especially interested in the role of RAS-oncogenes, which are an essential component of many intracellular signal transduction cascades. They are potent drivers of leukemia development and are frequently mutated in human myeloid leukemia patients.

Network: Our international research group is located at the Division of Pharmacology, the Center for Medical Research (ZMF), and the Division of Hematology. This setting enables direct interaction with both basic and clinical scientists. Moreover, the team actively collaborates with renowned national and international experts. Our research covers the whole spectrum of preclinical leukemia research, including studies in genetically engineered leukemia mouse models and leukemic cell lines, where we perform cutting-edge techniques, such as CRISPR/Cas9 genome editing. Finally, our research also provides a strong translational aspect, as we extend our work to primary human leukemia patient specimens.

Projects

The role of EZH2 mutations in RAS-mutated myeloid leukemias

Mutations in RAS and EZH2 frequently co-occur in myeloid leukemias. We could show that EZH2 mutations potentiate the leukemogenic effects of RAS mutations, which ultimately alters the sensitivity to RAS-signaling inhibitors (Berg JL et al., Leukemia 2021). In this project, we employ transgenic mouse models to comprehensively characterize the co-existence of RAS and EZH2 mutations and elaborate on novel therapeutic approaches for this genetic condition. Finally, we validate the clinical relevance of the results in primary patient specimens and ‘patient-derived xenograft’ transplantation models.
Duration: 2019-2023
Funded by: Leukämiehilfe Steiermark
Project partners (Med Uni Graz external): Klaus Geissler (Krankenhaus Hietzing, Wien), Michael Schuster & Thomas Penz (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Wien); international: Carsten Müller-Tidow (Universitätsklinikum Heidelberg, Deutschland), Karen Blyth (The Beatson Institute, Glasgow, UK), Veronica Caraffini (University of Cambridge, Cambridge, UK)

Non-coding RNAs as regulators of RAS-signaling and as mediator of therapeutic resistance in acute myeloid leukemia

miRNAs are non-coding RNAs and crucial regulators of cellular gene expression profiles. We and others previously demonstrated that aberrant expression of miRNAs is a crucial step in myeloid leukemogenesis and might even modulate the sensitivity to cytostatic therapies. In this project, we study the effects of deregulated miRNA expression on RAS signaling in myeloid neoplasms. We employ transgenic RAS-mutated mouse models and a series of in-vitro studies in leukemic cell lines. Finally, we validate the clinical relevance of the results in primary patient specimens.
Duration: 2019-2022
Funded by: Austrian Society of Internal Medicine (ÖGIM)
Project partners (Med Uni Graz external): Sascha Tierling (Universität des Saarlandes, Saarbrücken, Deutschland), Jakob Troppmair (Meduni Innsbruck)

Deciphering the pathogenesis of myeloid sarcoma

Acute myeloid leukemia (AML) is a systemic disease of the hematopoietic tissues. In some cases, leukemic cells infiltrate extramedullary tissues and grow as solid tumors, a situation referred to as ‘myeloid sarcoma’. We previously demonstrated that aberrant RAS-signaling contributes to the development of this specific AML subtype (Caraffini V et al., Blood 2018). In this project, we aim to further elaborate on the molecular pathogenesis of myeloid sarcoma and lay a specific focus on RAS-signaling aberrations.
Duration: 2019-2023
Funded by: Med Uni Graz
Project partners (Med Uni Graz external): Friedrich Stölzel (Universitätsklinikum Dresden, Dresden, Deutschland), Veronica Caraffini (University of Cambridge, Cambridge, UK)