Florian Grebien

Biology of Pediatric Leukemia Oncoproteins

We study the molecular mechanisms of leukemia development and progression to identify novel vulnerabilities of pediatric cancers. Using a wide array of cutting-edge technologies and state-of-the-art methods, we unveil how genetic mutations contribute to the development of cancer and investigate novel therapeutic strategies to exploit them as potential drug targets.

Our research

Leukemia is a cancer of white blood cells. The disease is characterized by the rapid accumulation of abnormal cells that interfere with the production of normal blood cells. Pediatric leukemias are often very aggressive and show limited response to current therapies. Leukemia-associated oncoproteins often arise from mutations in genes that encode transcription factors and epigenetic modulators.

We believe that the transforming properties of leukemia oncoproteins are hard-wired in specific networks of physical, genetic and epigenetic interactions with key effector genes and proteins. Functional exploration of these networks provides new insights into cellular processes that are hijacked by leukemia oncoproteins during leukemia development and maintenance.

The goal of our research is a comprehensive investigation of oncogenic mechanisms employed by leukemia oncoproteins to identify novel entry points for targeted treatments. In my lab, we study cellular and molecular effects of leukemia-associated oncoproteins through the development and use of novel tools and approaches, including, transcriptomics, proteomics, functional genomics and high-resolution imaging.

Fusion Oncoproteins

Chromosomal rearrangements often lead to the expression of fusion proteins, which can act as strong cancer drivers. As fusion oncoproteins are neomorphic protein variants with aberrant activities, they represent attractive targets for cancer therapy and have proven to be instructive subjects for cancer research. Fusion proteins are hallmarks of many childhood cancers and are frequently used to classify disease-defining entities in leukemia. We investigate how leukemia fusion oncoproteins hijack the cellular infrastructure to induce oncogenic gene expression programs using a multidisciplinary approach.

Approaches and models

While recent advances in our knowledge of the genomic makeup of most cancers have contributed significantly to our understanding of the origin and progression of the disease, it is still unclear how cancer-initiating molecular alterations are functionally integrated into higher-order cellular structures to realize oncogenic programs. By combining novel cell line and animal models of leukemia with cutting-edge proteomic-, epigenomic- and transcriptomic approaches, we perform a detailed functional characterization of leukemia oncoproteins in a global, multilayered fashion.

Genome-wide CRISPR/Cas9 screening is used to provide functional genomic context to biochemical and molecular biological observations. We use targeted protein degradation to investigate the dynamics of leukemia oncoprotein action in a time-resolved fashion. High-resolution imaging of their subcellular localization provides cellular context to leukemia oncoprotein activity. These analyses are complemented by functional studies in mouse models and primary human samples to detect molecular vulnerabilities that are dependent on the oncogenic mutation of interest.

Biosketch

Florian Grebien obtained his PhD from the Medical University Vienna under joint supervision of Ernst Müllner (Medical University Vienna) and Hartmut Beug (Research Institute for Molecular Pathology) in 2007. During his PhD studies, he studied the role of signalling pathways on erythrocyte differentiation. For his post-doctoral training he joined the team of Giulio Superti-Furga at CeMM. Using a combination of cell biology, protein biochemistry, and chemical biology, he identified molecular mechanisms that underlie oncoprotein-driven leukemia. From 2014 to 2018, Florian was a Principal Investigator and group leader at the Ludwig Boltzmann Institute for Cancer Research (LBI-CR) in Vienna, supported by an ERC Starting Grant. In January 2018, he was appointed Professor and head of the institute for Medical Biochemistry at the University of Veterinary Medicine Vienna. Florian joined the St. Anna Children’s Cancer Research Institute (CCRI) in February 2023 as a Principal Investigator and CeMM in Octobre 2023 as Adjunct PI. His research focuses on molecular mechanisms of oncoprotein-driven leukemia.

Selected Papers

Heyes E, et al. TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression. Nat Commun. 2023 Oct 4;14(1):6185. (abstract)

Ebner J, et al. ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia. Nat Commun. 2023 Sep 19;14(1):5709. (abstract)

Schmoellerl J. et al. EVI1 drives leukemogenesis through aberrant ERG activation. Blood, 2023 Feb 2;141(5):453-466. (abstract)

Eder T, Grebien F. Comprehensive assessment of differential ChIP-seq tools guides optimal algorithm selection. Genome Biol, 2022 May 24;23(1):119. (abstract)

Terlecki-Zaniewicz S, et al. Biomolecularcondensation of NUP98 fusion proteins drives leukemogenic gene expression. Nat Struct Mol Biol, 2021 Feb;28(2):190-201. (abstract)

Schmoellerl J, et al. CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia. Blood, 2020 Jul 23;136(4):387-400. (abstract​​​​​​​)