New Analytical Method Reveals How Specific RNA Molecules Shape Aggressive Leukemia

Researchers at the University of Veterinary Medicine Vienna, working alongside teams at the CeMM Research Center for Molecular Medicine and St. Anna Children’s Cancer Research, have introduced a novel analytical technique to uncover how specific RNA molecules interact with cancer-promoting structures inside cells. Published in The EMBO Journal, the investigation sheds light on aggressive forms of acute myeloid leukemia and highlights potential avenues for future oncology research.

Investigating Oncocondensates in Acute Myeloid Leukemia

Aggressive forms of leukemia can be driven by fusion oncoproteins. Inside cellular environments, these proteins can accumulate within biomolecular condensates. These dynamic, membrane-less structures allow various biomolecules to interact and regulate gene activity. Until now, tracking which exact RNA molecules associate with these oncocondensates remained challenging.

To overcome this hurdle, the Vienna-based research team designed a method known as bicon-seq. Senior study author Florian Grebien, head of the Unit of Medical Biochemistry at the University of Veterinary Medicine Vienna, explained that the approach systematically identifies RNAs associated with biomolecular condensates, measuring a previously difficult layer of gene regulation.

The Role of the lncRNA Gas5

The study specifically examined the fusion oncoprotein NUP98::KDM5A, which appears in aggressive cases of acute myeloid leukemia and helps form condensates required to activate leukemia-relevant genes. Using bicon-seq, the researchers obtained quantitative data regarding cellular RNA solubility, allowing them to track how condensate composition shifts when key components are disrupted.

The analyses highlighted several long noncoding RNAs linked to NUP98::KDM5A condensates. Among them, the long noncoding RNA known as Gas5 stood out. According to the findings, Gas5 was heavily expressed in the leukemia cells, co-localized with NUP98::KDM5A within the condensates, and proved essential for the proliferation of the cancer cells.

• Bicon-seq tracked RNA solubility and composition changes within biomolecular condensates.
• Gas5 co-localized with the NUP98::KDM5A fusion protein in leukemia cells.
• Targeted suppression of Gas5 altered the gene activity of acute myeloid leukemia cells.

Targeted Gene Suppression Insights

To evaluate the function of Gas5, first author Melanie Allram and colleagues utilized CRISPRi, a method for targeted gene suppression. When Gas5 was specifically downregulated, the gene activity within the acute myeloid leukemia cells shifted substantially. The affected genes included those responsible for cellular differentiation and programmed cell death, demonstrating that Gas5 acts as more than just a passive component of the condensates.

While these findings provide fundamental insights into RNA biology and fusion oncoproteins, the authors emphasize that further research is necessary. The Grebien Lab plans to continue examining how the precise interaction between Gas5 and the NUP98::KDM5A fusion protein governs gene activity and influences leukemia development.