A new study published in PNAS has shown that the tumour-inhibiting gene TET2 is silenced in a large fraction of cases of acute lymphoblastic leukaemia (ALL) in children. The scientists show that the gene can be reactivated by an existing drug, 5-azacytidine, suggesting that it could be used a as targeted therapy for ALL in children.
“T-cell acute lymphoblastic leukaemia (T-ALL) is a devastating disease for the affected children and their families. One of five children affected do not survive the disease. The ultimate goal of my research is to ensure that all children can be cured. Our discovery may pave the way for clinical studies of 5-azacytidine as a new therapy for this poorly understood disease. The more treatment options we have for T-ALL the more chance we have of beating this aggressive cancer,” explained study leader Colm Nestor, senior lecturer in the Department of Biomedical and Clinical Sciences .
One of the characteristics of cancer cells is that they lose their cellular identity. One of the reasons for this is certain genes being silenced while others are activated. Switching genes on and off is controlled by epigenetic modification, where small chemical groups are attached to and removed from DNA, such as DNA methylation. The pattern of DNA-methylation is often altered in cancer cells, making them attractive targets for cancer drug research.
In the recently published study, the researchers were interested in an enzyme, TET2, that removes methyl groups from DNA. The gene that codes for TET2 is often affected by mutations in adult leukaemias. In children however, harmful mutations in TET2 are very rare, which led the researchers to speculate whether TET2 function is affected differently in child leukaemias. They analysed the gene expression patterns in cancer cells from more than 300 patients with T-ALL, and found that in many cases the TET2 gene was silenced.
It turned out that methylation often silenced the TET2 gene. The scientists therefore decided to treat tumour cells in culture with a drug, 5-azacytidine, that removes methyl groups from DNA. This drug is used to treat certain leukaemias in adults.
“We found that one type of T-ALL cell, whose DNA seems to be highly methylated, is more sensitive to azacytidine than other cells that are not highly methylated. The drug actually turns silenced TET2 back on by demethylating it, so this might be a targeted therapy for a subset of cases. We suggest that azacytidine may have a doubled effect in these cells, since both the drug itself and TET2 kill cancer cells by demethylating the genome,” explained Colm Nestor.
Since 5-azacytidine is an approved drug, the researchers hope that it will be a much quicker path to treatment than when developing a novel drug.
“Chemotherapy agents have a broad effect and can be used for many patients, but they also kill healthy cells and can give rise to serious undesired effects. Targeted treatment, on the other hand, only works for a small fraction of patients, but is extremely specific. We need an arsenal of drugs to use for patients who experience relapses, and for those whose cancer does not respond to chemotherapy,” said Colm Nestor.
The researchers will continue with experiments to determine the effects of activating TET2 in these cancer cells, and to see if 5-azacytidine can function as targeted therapy in other types of cancer.
“The fact that we can target the loss of TET2 using the drug 5-azacytidine makes me hopeful that this treatment can help T-ALL patients in the future,” said researcher Maike Bensberg, PhD student at Linköping University.
Source: Linköping University
