Cancer-associated chromosomal rearrangements often result in the expression of pathogenic fusion proteins. Leukaemia features a particularly high frequency of fusion oncogenes, and the functional investigation of leukaemia-associated fusion proteins has provided invaluable insights into the molecular mechanisms of cancer development. The protein complexes around fusion proteins play a defining role in shaping oncogenic gene expression patterns, and the investigation of protein interactions is therefore crucial to identifying new targets on the basis of which to develop more effective cancer therapies.
Extremely poor prognosis for children with AML
While the most common leukaemia fusion proteins have been extensively characterized, functional understanding of rare fusions that affect a significant number of patients and have limited treatment options is still lacking. In acute myeloid leukaemia (AML), the N-terminal part of the Nucleoporin 98 (NUP98) gene (N-NUP98) is fused to over 30 different C-terminal partner loci. While NUP98 rearrangements are rare (accounting for about 2% of all AML), they are over-represented in paediatric AML, where they are associated with a particularly poor prognosis.
How NUP98-fusion proteins drive AML
All NUP98-fusion proteins share an intrinsically disordered region (IDR) in the NUP98 N-terminus featuring repeats of phenylalanine-glycine (FG), whereas C-terminal fusion partners often function in gene control. The researchers investigated whether the protein interactomes of NUP98-fusion proteins provided any insights into the mechanisms of oncogenic transformation. “Analyses of affinity purification coupled to mass spectrometry and confocal imaging of five different NUP98-fusion proteins revealed that shared interactors were enriched for proteins involved in biomolecular condensation. These factors colocalized with NUP98-fusion proteins in characteristic condensates in the cell nucleus,” says study director Florian Grebien, Head of the Institute for Medical Biochemistry at the University of Veterinary Medicine Vienna. An artificial FG fusion protein phenocopied the nuclear localization patterns of NUP98-fusion proteins and their capability to drive oncogenic gene expression programmes.
New starting point for improved cancer therapies
The researchers used a newly developed method called biotinylated isoxazole-mediated condensome mass spectrometry (biCon-MS) to show that NUP98-fusion proteins alter the global composition of biomolecular condensates to drive oncogenic gene expression programmes. “On the basis of the data gathered in this study, we propose that IDR-containing fusion proteins combine biomolecular condensation with transcriptional control to induce cancer,” explains first author Stefan Terlecki-Zaniewicz from the Institute for Medical Biochemistry at Vetmeduni Vienna and Children’s Cancer Research Institute. The alteration of biomolecular condensation could therefore be a fundamental principle of cancer development driven by oncogenic fusion proteins. The researchers believe this could be a new approach to developing more effective and targeted cancer therapies.
Contact
Florian Grebien
Institute for Medical Biochemistry
University of Veterinary Medicine Vienna (Vetmeduni Vienna)
T +43 (1) 25077-4200
Florian.Grebien(at)vetmeduni.ac.at
Stefan Terlecki-Zaniewicz
Epigenome-based Precision Medicine
St. Anna Kinderkrebsforschung GmbH
CHILDREN'S CANCER RESEARCH INSTITUTE / CCRI
T +43 (1) 40470-4034
stefan.terlecki-zaniewicz(at)ccri.at
Nina Grötschl
Science Communication / Corporate Communications
University of Veterinary Medicine Vienna (Vetmeduni Vienna)
T +43 1 25077-1187
Nina.Groetschl(at)vetmeduni.ac.at