New research has discovered how genetic mutations hijack blood cell production at different times of life. Scientists from the Wellcome Sanger Institute, Cambridge Stem Cell Institute, EMBL European Bioinformatics Institute (EMBL-EBI) and collaborators show how these changes relate to aging and the development of age-related diseases , including blood cancer.
The new study, published today (June 1) in Naturerepresents the first time that the lifelong impact of genetic mutations on cell growth dynamics has been explored.
All human cells acquire genetic changes in their DNA throughout their lives, called somatic mutations, with a specific subset of mutations causing cells to multiply. This is common in professional blood-producing cells, called blood stem cells, and results in the growth of populations of cells with identical mutations called ‘clones’. This process, called “clonal hematopoiesis,” becomes pervasive with age and is a risk factor for developing blood cancer and other age-related conditions.
To understand how and when clonal hematopoiesis develops, how it is influenced by aging and how it is linked to disease, the researchers followed nearly 700 blood cell clones from 385 people over the age of 55, who were part of the SardiNIA longitudinal study. The participants gave blood samples regularly for 16 years.
DNA sequencing of blood samples showed that 92.4% of the clones grew at a stable exponential rate over the study period. The growth rate was mainly influenced by the nature of the mutated gene in each clone.
After capturing the clones’ behavior later in life, the team used mathematical models to infer their growth patterns throughout human life. They found that the clones’ behavior changed dramatically with age depending on the identity of the mutated gene.
First, clones induced by mutations in DNMT3Agrew rapidly in youth, then decelerated in old age. Second, clones driven by mutations in TET2 appeared and grew evenly throughout life, so they became more frequent than DNMT3A– mutant clones after 75 years. Finally, the clones carrying mutations in the splicing genes, U2AF1 and SRSF2did not develop until later in life and exhibited one of the fastest growths.
These age-dependent clonal behaviors reflect the frequency of emergence of different types of blood cancers and reveal that mutations associated with rapid clonal growth are more likely to lead to malignancy.
Our findings reveal how acquired genetic changes hijack blood formation during our lifetime, as normal blood stem cells compete with cells carrying pre-leukemic mutations. Understanding why certain mutations are prevalent in young people and others in old people could help us find ways to maintain the health and diversity of our blood cells.”
Dr Margarete Fabre, lead researcher of the study and PhD student at the Wellcome Sanger Institute and the University of Cambridge
Study co-lead author Dr Moritz Gerstung, from EMBL’s European Institute of Bioinformatics and the German Cancer Research Center (DKFZ), said: “For the first time, we were able to using genomic analysis to understand the past, present and future. mutant clones in our blood. 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 yet understand.
Study co-lead author Professor George Vassiliou, formerly of the Wellcome Sanger Institute, and now Professor of Haematological Medicine at the Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge and Cambridge University Hospitals, said “Collectively, our work reveals an amazing interplay between aging and DNA mutations in our blood cells that results in 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.
Fabre, MA, et al. (2022) The longitudinal dynamics and natural history of clonal hematopoiesis. Nature. doi.org/10.1038/s41586-022-04785-z.
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