Existing drug may work as targeted therapy for ALL in children

A new study from Linköping University has shown that the TET2 tumor inhibitor gene is silenced in a large part of cases of acute lymphoblastic leukemia (ALL) in children. Scientists show that the gene can be reactivated by treatment with an existing drug, 5-azacytidine. The results, published in the scientific journal PNAS, suggest that 5-azacytidine may work as a targeted therapy for ALL in children.

“Acute T-cell lymphoblastic leukemia (ALL-T) is a devastating disease for affected children and their families. One of the five affected children does not survive the disease. The ultimate goal of my research is to ensure that all children can be healed. . Our discovery could 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 likely we are to beat this aggressive cancer, ”says Colm Nestor, senior lecturer in the Department of Biomedical and Clinical Sciences at Linköping University, who led the study.

One of the characteristics of cancer cells is that they lose their cellular identity. It is as if they have forgotten that they should be, for example, a liver cell, a brain cell or an immune system cell. One of the reasons for this loss of identity is that genes that should be active in a certain type of cell have been turned off (silent), while other genes have been turned on by mistake. The activation and deactivation of genes is controlled by a process known as epigenetic modification, in which small chemical groups are attached and removed from DNA. One of these epigenetic changes is DNA methylation. It has long been known that the DNA methylation pattern is often altered in cancer cells, and for this reason, drugs that alter DNA methylation are of interest as potential cancer treatments.

In the recently published study, researchers looked at an enzyme, TET2, which removes methyl groups from DNA. The gene that codes for TET2 is often affected by mutations in adult leukemia. In contrast, harmful mutations in TET2 are very rare in T-ALL in children. This has led researchers to speculate whether the function of TET2 is affected in a different way in childhood leukemia. They analyzed the patterns of gene expression in cancer cells from more than 300 T-ALL patients and found that the TET2 gene was silenced in a large part of the cases.

It turned out that the TET2 gene was often silenced by methylation. Scientists therefore decided to treat cultured tumor cells with a drug, 5-azacytidine, which removes methyl groups from DNA. This medicine is used to treat certain leukemia in adults.

We have found that a type of T-ALL cell, whose DNA appears to be highly methylated, is more sensitive to azacytidine than other cells that are not strongly methylated. The drug actually reactivates the silent TET2 by demethylating it, so it could be targeted therapy for a subset of cases. We suggest that azacytidine may have a doubled effect in these cells, since the drug itself and TET2 kill cancer cells by demethylating the genome. “

Colm Nestor, Senior Lecturer, Department of Biomedical and Clinical Sciences, Linköping University

Since 5-azacytidine has already been approved as a drug, the researchers hope that the path from preclinical laboratory results to actual treatment of children with T-ALL will be much shorter than what is needed at the time of treatment. development of a new drug.

“Chemotherapy drugs have a wide effect and can be used for many patients, but they also kill healthy cells and can cause serious side effects. Targeted therapy, on the other hand, only works for a small fraction of patients, but is extremely. », Explains Colm Nestor.

The research is still in its early stages. LiU researchers will now continue their experiments to determine the effects of TET2 activation in these cancer cells. Another question is whether 5-azacytidine may work as a targeted therapy in other types of cancer. The research group hopes their discovery will inspire other researchers to test the therapy in clinical studies.

“The fact that we can target the loss of TET2 using the drug 5-azacytidine gives me hope that this treatment can help T-ALL patients in the future,” says Maike Bensberg, PhD student at Linköping University and one of the researchers behind the study.