14 June 2022

British researchers have revealed mechanisms behind genetic mutations that affect blood cell production over a lifetime. The findings provide vital clues about the development of leukaemia.

Scientists at the Wellcome Sanger Institute, the Cambridge Stem Cell Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI) have discovered for the first time how these changes relate to ageing and the development of age-related diseases, including blood cancer.

Writing in Nature, they show the lifelong impact of genetic mutations on cell growth dynamics.

To understand how and when clonal haematopoiesis develops, how it is influenced by ageing, and how it relates to disease, the researchers tracked nearly 700 blood cell clones from 385 individuals aged over 55.

They were all part of the SardiNIA longitudinal study and had donated regular blood samples for up to 16 years.

When blood samples underwent DNA sequencing, it was found that 92.4% of clones expanded at a stable exponential rate over the study period. The rate of growth was primarily influenced by the nature of the mutated gene in each clone.

After capturing the behaviour of clones in later life, the team went on to use mathematical models to infer their growth patterns over the entire human lifespan. They discovered that clone behaviour changed dramatically with age depending on the identity of the mutated gene.

Lead researcher Margarete Fabre, PhD student at the Wellcome Sanger Institute and the University of Cambridge, said: “Our findings reveal how acquired genetic changes hijack blood formation during our lifetimes, with normal blood stem cells competing against cells with pre-leukaemia mutations. Understanding why some mutations prevail in youth and others in old age could help us find ways to maintain the health and diversity of our blood cells.”

The team found that clones driven by mutations in DNMT3A expanded quickly in young people and then decelerated in old age, while clones driven by mutations in TET2 appeared and grew uniformly throughout life to become more common than DNMT3A-mutant clones after the age of 75.

Clones with mutations in splicing genes U2AF1 and SRSF2 only expanded later in life and were among the fastest growing.

The team found that age-dependent clonal behaviours mirror the frequency of emergence of different types of blood cancers. They also discovered that mutations associated with fast clonal growth are more likely to lead to malignancy.

Co-senior study author Dr Moritz Gerstung, of EMBL’s European Bioinformatics Institute and the German Cancer Research Centre (DKFZ), said: “These data show that the dynamics of blood clones are surprisingly predictable over a period of years, but also highlight that they change over a lifetime in ways we don't understand yet.”

Professor George Vassiliou, also co-senior author of the study and now professor of haematological medicine at the Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, and Cambridge University Hospitals, added: “Collectively, our work reveals an astonishing interaction between advancing age and mutations in the DNA of our blood cells that is played out as the expansion of cells with different mutations at different ages.

“Remarkably, these changes lead to the emergence of different types of blood cancers at different ages, and with different risks of progression. With this new understanding, researchers can begin to develop approaches and treatments to stop the development of blood cancer in its tracks.”

Source: Fabre MA, de Almeida JG, Fiorillo E, Mitchell E, Damaskou A, Rak J, Orrù V, Marongiu M, Chapman MS, Vijayabaskar MS, Baxter J, Hardy C, Abascal F, Williams N, Nangalia J, Martincorena I, Campbell PJ, McKinney EF, Cucca F, Gerstung M, Vassiliou GS. (2022) “The longitudinal dynamics and natural history of clonal haematopoiesis.” Nature, doi: 10.1038/s41586-022-04785-z

Link: https://www.nature.com/articles/s41586-022-04785-z

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