Scientists from the Princess Máxima Center for pediatric oncology have found that, in some children with acute myeloid leukemia (AML), cancer cells have the same amount of DNA changes as healthy blood stem cells. Surprisingly, these children have a poorer chance of survival compared to children whose leukemia has an above-average number of DNA changes.
This new study offers insight into how this form of blood cancer can develop in children and may lead to new ways of identifying which patients have a high-risk form of the disease.
The researchers compared the complete DNA of healthy blood stem cells with that of leukemia cells using biopsies from the bone marrow of children treated for AML from the Máxima and internationally available data from 90 children. Their study was published on Thursday 5 August in the journal Blood Cancer Discovery.
Somatic mutations accumulate throughout life, which is believed to be the reason older people suffer more cancers. However, some cancers, such as leukemia and brain tumors, show a relatively high incidence in young children. Further, pediatric cancers display fewer cancer driver mutations compared with adult cancers. This has led the hypothesis that pediatric cancers have a different origin than adult malignancies.
As the authors note, “Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults.” They compared somatic mutations across pediatric AML patient-matched leukemic blasts and hematopoietic stem and progenitor cells (HSPC), as well as HSPCs from age-matched healthy donors.
The researchers point out that HSPCs in the leukemic bone marrow have limited genetic relatedness and share few somatic mutations with the cell of origin of the malignant blasts, suggesting polyclonal hematopoiesis in patients with pediatric AML. They write “Compared with normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize that these cases might have arisen from a more committed progenitor. This subset had better out- comes than pAML cases with mutation burden comparable with age-matched healthy HSPCs.”
“We saw that in some children, the amount and types of DNA changes in leukemia cells was very different from what we see in healthy blood stem cells,” said Ruben van Boxtel, principal investigator at the Princess Máxima Center. The leukemia cells in these children had many more DNA faults compared to healthy blood stem cells, due to oxidation.
The children in this group had a better chance of survival compared to children who had the same number of DNA changes in the leukemia and healthy blood stem cells. “That was surprising,” said van Boxtel. “DNA changes are what make cancer malignant. With more of these changes, you would expect a worse outcome.” When the team looked into more detail, they found that in these children, AML probably started in more specialized blood cells that are less likely to become malignant.
In the future, the amount of DNA faults in blood stem cells could help identify high- or low-risk forms of AML in children, Van Boxtel hopes. “Instead of looking for specific DNA changes, we would then only need to measure the amount and type of DNA damage in the blood stem cells. That is a very easy test, for which we don’t need to draw extra blood.” A lot of further research is still needed, but this is the beginning, he explained. “We are an important step closer to understanding of the origin of AML in children.”
