University of Veterinary Medicine
Institute for Medical Biochemistry
Website Grebien lab
”Oncogenic mechanisms of fusion proteins in cancer - Lessons from protein modules”
Fusion proteins are found in adult and pediatric leukemia with poor prognosis, and they frequently act as oncogenic drivers. Despite intense research, a detailed understanding of the molecular mechanisms that underlie fusion-protein-driven leukemia is lacking, and this has prevented the development of effective targeted therapies. We have developed innovative mouse and cell line models to study molecular pathways that govern the development and maintenance of fusion-proteins that drive high-risk leukemia. The NUP98 (Nucleoporin 98) gene is fused to >25 partner genes in AML, ALL and MDS, and NUP98-fusion-driven leukemia is associated with particularly poor outcomes in children. Using mouse models of Tetracycline-regulatable fusion protein expression, we identified conserved transcriptional programs that underlie NUP98-fusion mediated oncogenesis. Via a combination of Mass Spectrometry and confocal imaging, we found that NUP98-fusion proteins form biomolecular condensates in the nuclei of AML cells. These chromatin-associated structures contain essential transcriptional activators and their formation is critical for the induction of oncogenic gene expression programs. To characterize direct epigenetic and transcriptional effects of NUP98-fusion proteins in AML, we established a model for ligand-induced degradation of NUP98::KDM5A. CUT&Tag, nascent mRNA sequencing and data from a genome-wide CRISPR/Cas9 screen revealed direct transcriptional target genes of NUP98::KDM5A that are essential for AML cell proliferation. Our current work focuses on mechanistic studies of transcriptional effectors of NUP98-fusion driven oncogenesis in cell lines, mouse models and primary patient cells.
Host: Johannes SCHMID
Contact for questions: Helmut KUBISTA