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New insights into the development of relapsed leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer worldwide. Although the chance of recovery is high, a number of children suffer a relapse. Scientists from St. Jude Children's Research Hospital, UMC Utrecht and the Princess Máxima Center investigated the relapse tumor cells after treatment.
For this study, the DNA of the cancer cells was tested in 92 children at diagnosis as well as at relapse. The researchers searched for the differences in DNA before and after treatment and published their findings in the scientific journal Blood Cancer Discovery.

Origin of the relapse
The scientists saw that in the relapse tumor cells, the number of errors in the DNA, so-called mutations, is higher than at time of diagnosis. ‘We analyzed the DNA in detail, which enabled us to map the diversity of cells in the tumor’, explains Esmé Waanders, first author of the article and laboratory specialist clinical genetics (UMC Utrecht).

With this information Waanders and her colleagues determined the origin of the relapse cells. ‘In almost all cases we found that the relapse cells were already present at the time of diagnosis’, says Waanders, ‘which means that the treatment given was not able to destroy these cells.’ The next step is a much more intensive treatment than the one following diagnosis.

In three children, the researchers saw that the cells were not yet present at the time of diagnosis. ‘This means that the second leukemia in these children developed independently, possibly as a result of the treatment or genetic predisposition’, says Waanders. ‘We then speak of a new cancer. This is important because in hind sight a milder treatment regimen might have sufficed in these children.’

Relapse-specific DNA abnormalities
The detailed approach of the DNA analysis provided crucial information about the processes that were specifically disrupted in the relapse cells. It is possible to detect the presence of these specific abnormalities in the DNA of the bone marrow of children. In this study the scientists developed a new highly sensitive technique for this purpose. ‘This means that the bone marrow of children in remission can be tested for this’, says Waanders, ‘it is a good technique to monitor the disease, because the presence of these relapse-specific mutations can possibly predict the recurrence of the disease.’

In some cases, the number of mutations in the DNA of the relapse leukemia cells was extremely high compared to the number at diagnosis and the scientists spoke of hypermutation. ‘This was an unexpected discovery for us’, says Roland Kuiper, research group leader at the Princess Máxima Center and senior author of the article, ‘especially because leukemia cells normally have very few mutations.’

Further research showed that not one, but at least four mechanisms can be the underlying cause of hypermutation, sometimes even in combination. Two of these four mechanisms have already been described in other forms of cancer, but the other two could not yet be explained. ‘This is particularly fascinating’, according to Kuiper, ‘because the leukemia cell has in fact undergone a metamorphosis compared to the initial diagnosis. We want to study this further in order to better understand the origins of relapse.’

Monitoring and treatment
In the future this research can lead to better monitoring of the children after treatment and a more targeted approach in case of disease relapse. ‘You have to know what the problem is before you can do something about it’, says Waanders. ‘The study has given us considerable insight into the properties of a relapse leukemia cell.’