Researchers Find Insight Into Risk of Developing AML

As people age, they accumulate mutations in hematopoietic stem cells, carrying a risk for hematologic malignancies like acute myeloid leukemia (AML); however, why some people with these accumulated mutations, through a process called age-related clonal hematopoiesis (ARCH), develop AML and others do not has remained unclear.

In a recent study, researchers, using deep learning and population genetics, were able to show how different evolutionary forces in aging blood stem cells impact whether or not someone develops AML, offering insight into those at higher risk of the disease.

Their findings were recently published in Nature Communications.

"We have shown that the constellation of evolutionary forces at play within hematopoietic stem cells can be a robust indicator of those who are at increased risk of blood cancers such as AML," said Philip Awadalla, PhD, senior principal investigator and director, Computational Biology, at the Ontario Institute for Cancer Research, in a statement. "Being able to accurately classify patients based on risk can allow for more frequent and intensive screening for those with ARCH mutations with a concerning evolutionary signature."

The researchers analyzed blood samples, which had undergone deep genomic sequencing, from 92 patients who developed AML and 385 patients who did not develop AML despite having ARCH. Through their approach, they were able to discriminate signatures of negative selection from neutrality and investigate the impact of positive and negative mutations on patterns of clonal dominance among the samples.

By studying the interaction between positive, neutral, and negative evolutionary selection on the mutations within the blood stem cells, the group determined an important role of negative selection acting on mutations in nondriver genes. They also found that mutations accumulate along with ARCH-associated driver mutations and that the rate of clonal expansions may be slowed by negative selection acting on linked passenger mutations.

“The presence of negative selection acting on passenger mutations in the presence of driver mutations offers a potential explanation for why some individuals who harbor driver mutations do not progress to disease,” explained the researchers. “However, negative selection appears to play an important role in lowering the overall pathogenicity of the mature blood cell pool, thus maximizing the fitness of the individual, a finding which suggests that there could be an advantage to retaining mildly damaging mutations in cellular populations if they confer a protective effect in the presence of a driver mutation.”

Altogether, they believe, their findings may enable better identification of individuals with a high malignancy risk.

Reference

Skead K, Houle AH, Abelson S, et al. Interacting evolutionary pressures drive mutation dynamics and health outcomes in aging blood. Nat Commun. Published online August 13, 2021. doi:10.1038/s41467-021-25172-8