Florian Grebien

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

Leukemia is a hematologic cancer affecting 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, such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), are often very aggressive and show limited response to current therapies. Leukemia-associated oncoproteins frequently arise from mutations in genes that encode transcription factors and epigenetic regulators.

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

The goal of our research is a comprehensive investigation of the oncogenic mechanisms employed by leukemia-associated fusion proteins and other oncoproteins to identify novel entry points for precision oncology and targeted leukemia treatments. In our lab, we study cellular and molecular effects of leukemia oncoproteins through the development and use of advanced 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 potent cancer drivers. These fusion oncoproteins are neomorphic protein variants with aberrant biological activities and represent attractive therapeutic targets in pediatric cancer research. Fusion proteins are hallmarks of many childhood leukemias and are frequently used to classify disease-defining subtypes in leukemia. We investigate how leukemia fusion oncoproteins hijack cellular infrastructure to induce oncogenic transcriptional programs, applying a multidisciplinary cancer research approach.

Approaches and Models

While recent advances in cancer genomics have significantly expanded our understanding of the origin and progression of various cancers, it remains unclear how molecular alterations in leukemia are functionally integrated into higher-order cellular architectures to activate oncogenic programs. By combining novel leukemia cell lines and animal models with cutting-edge proteomic, epigenomic, and transcriptomic technologies, we perform detailed, multilayered functional characterization of leukemia-relevant oncoproteins.

Genome-wide CRISPR/Cas9 screening provides functional genomic context to biochemical and molecular observations. We apply targeted protein degradation to dissect the dynamics of leukemia oncoprotein action in a time-resolved manner. High-resolution cell imaging of their subcellular localization gives valuable insight into the cellular context of oncoprotein function. These analyses are complemented by functional studies in murine leukemia models and primary human samples to detect molecular vulnerabilities that depend on specific oncogenic mutations in pediatric leukemia.

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.

Kodali S, Proietti L, et al. RNA sequestration in P-bodies sustains myeloid leukaemia. Nat Cell Biol, 2024 Oct;26(10):1745-1758. (abstract).

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. Biomolecular condensation 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​​​​​​​)