Every year, around 25 children in the Netherlands are diagnosed with acute myeloid leukemia (AML), a form of blood cancer. Survival rates have improved in the last decades, and more than 70% of children now survive their disease. But the chemotherapy treatment can lead to long-term side effects, and smarter, kinder treatments are needed.
In many children with AML, the disease is caused by chromosomal rearrangements that fuse two genes together. These so-called fusion genes drive the cancer and are therefore a promising target for treatment. Yet so far, it has been unclear whether fusion gene silencing would work in real patient cells, and what effects it might have.
Healthy-like cells
Researchers from the Heidenreich group investigated what happens when the fusion gene RUNX1::RUNX1T1 is switched off in primary AML cells from children. Using a special culture method, they kept AML cells taken from blood samples of children treated at the Princess Máxima Center alive in the lab for several weeks. Using tiny fat droplets, called lipid nanoparticles, the researchers delivered siRNA to the cells, a technique that can switch off specific genes by ‘silencing’ them. Former PhD student and co-first author of the study Laura Swart developed the delivery vehicle.
Using single-cell RNA sequencing, the team discovered that silencing the fusion gene led the cells to split into two types. One group developed into granulocyte-like cells, which closely resemble healthy immune cells. The second group had a so-called eosinophilic-like identity. Eosinophils are involved in immune processes such as combating parasites and triggering allergic responses.
‘It was exciting to see that silencing of the fusion gene turned leukemic cells toward normal immune cells,’ says Polina Derevyanko, PhD student and co-first author of the study. ‘At the same time, we don’t yet know enough about these healthy-like cells. Next, we plan to examine them if and how these more normal cells affect the risk of relapse.’
Promising and realistic
The results offer an early but promising view on the potential of siRNA as a therapy for children with AML. Next, the Heidenreich group planned follow-up studies aiming at implementing such siRNA nanoparticles in the treatment of AML with the purpose to provide more targeted, less toxic cure for children with this form of blood cancer.
‘This is the first time we see such clear effects of fusion gene knock-down in primary AML cells from patients,’ says Prof. Dr. Olaf Heidenreich. ‘It highlights the power of siRNA as a targeted tool in leukemia, and gives us a new angle to pursue more effective therapies for children with AML.’
This research was published in the journal Blood and was made possible thanks to the Maarten van der Weijden Stichting in collaboration with Stichting Kinderen Kankervrij (KiKa).