Novel therapy against aggressive, poor-prognosis blood cancer

Acute myeloid leukaemia (AML) is an aggressive blood cancer that affects people of all ages. In cases with a particularly poor prognosis, AML is triggered by oncogenic fusion proteins whose formation involves the Nucleoporin 98 (NUP98) gene. A study by researchers from the Vetmeduni Vienna now presents a new therapeutic approach to combat this disease. According to the researchers, therapeutic interventions already approved for treating other types of cancer also work with this form of AML. The work was recently published in the renowned journal Blood.

Genetic rearrangements involving the NUP98 gene are rare genetic events that are recurrently found in AML and are associated with a particularly poor prognosis – especially if they occur in children and adolescents. Now a collaborative study between researchers from the Institute for Medical Biochemistry and the Institute of Pharmacology and Toxicology at Vetmeduni Vienna, with the participation of international research groups, has for the first time identified genes that are directly activated by NUP98 fusion proteins.

Simulation of AML in mouse models

To study the molecular mechanisms of NUP98 fusion proteins, Johannes Schmöllerl, first author of the study and a member of the research team at the Institute for Medical Biochemistry at Vetmeduni Vienna, generated several novel mouse models. For this purpose, he collaborated with Inês Barbosa from the laboratory of Johannes Zuber at the Research Institute of Molecular Pathology (IMP) at Vienna BioCenter. “These novel model systems allowed us to molecularly investigate the disease to an extent that was not previously possible. In addition, we were able to test new experimental therapies that are urgently needed in the clinical setting,” says Johannes Schmöllerl.

Therapeutic interventions approved for other types of cancer also work with AML

“When we analysed the data obtained from the mouse models, we found that NUP98-fusion oncogenes directly activate the expression of the enzyme CDK6. This is remarkable because molecular inhibitors that act directly on CDK6 are already being used in the clinical setting to treat other types of cancer,” explains Florian Grebien, senior author of the study and head of the Institute for Medical Biochemistry at Vetmeduni Vienna.

To more closely examine CDK6 in the context of a new therapeutic approach, the research team collaborated with the Veronika Sexl lab from the Institute of Pharmacology and Toxicology at Vetmeduni Vienna. Together they found that CDK6 inhibition has a very strong effect on patient-derived leukaemia cells with NUP98 fusion proteins. In the NUP98 fusion leukaemia mouse model, treatment with CDK6 inhibitors significantly improved the survival of the animals. Further clinical studies are now required to confirm the effectiveness of targeted CDK6 inhibition in patients with AML.

AML: cancer with a poor prognosis

Genetic changes involving the NUP98 gene are recurrently found in AML and are associated with poor prognosis, especially in young patients. Due to large chromosome aberrations, part of the NUP98 gene is fused with other genes on different chromosomes, leading to the expression of new chimeric proteins. These so-called fusion proteins do not normally exist in healthy cells and often act as strong oncogenic drivers – also in AML. Since there are no human cell lines that can be used to study NUP98 fusion proteins, the molecular details of how NUP98 fusion proteins lead to leukaemia had previously been unknown. The present study has now succeeded for the first time in shedding light onto this question while making a significant contribution to understanding the development of AML and developing therapies to fight the disease.

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