RTFCCR grantee update: Impact of DNA mutations on lifelong blood cell production uncovered

Researchers discover how leukaemia-associated gene mutations steadily commandeer blood cell production over a lifetime, and how these changes relate to ageing and cancer development.

New research by scientists at the Wellcome Sanger Institute, the Cambridge Stem Cell Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI) and collaborators has uncovered how genetic mutations hijack the production of blood cells in different periods of life, and how these changes relate to ageing and the development of age-related diseases, including blood cancer. 

The new study, published today (1st June) in Nature, represents 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 life, known as somatic mutations, with a specific subset of mutations driving cells to multiply. This is common in professional blood making cells, known as blood stem cells, and results in the growth of populations of cells with identical mutations known as ‘clones’. This process, termed ‘clonal haematopoiesis’, becomes ubiquitous with age, and is a risk factor for developing blood cancer, and other age-related conditions.

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, who were part of the SardiNIA longitudinal study. Participants donated regular blood samples for up to 16 years.

DNA sequencing of blood samples showed that 92.4 per cent of clones expanded at a stable exponential rate over the period studied. 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 used mathematical models to infer their growth patterns over the entire human lifespan. They uncovered that clone behaviour changed dramatically with age depending on the identity of the mutated gene. First, clones driven by mutations in DNMT3A, expanded fast in young people and then decelerated in old age. Second, clones driven by mutations in TET2 appeared and grew uniformly throughout life, such that they became more common than DNMT3A-mutant clones after the age of 75. Finally, clones with mutations in splicing genes, U2AF1 and SRSF2, only expanded exclusively later in life and exhibited some of the fastest growth.

These age-dependent clonal behaviours mirror the frequency of emergence of different types of blood cancers and reveal that mutations associated with fast clonal growth are more likely to lead to malignancy.

Dr Margarete Fabre, lead researcher on the study and PhD student at the Wellcome Sanger Institute and the University of Cambridge, said: “Our findings reveal how acquired genetic DNA 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.”

Dr Moritz Gerstung, co-senior author of the study, from EMBL’s European Bioinformatics Institute and the German Cancer Research Centre (DKFZ), said: “For the first time we have been able to use genomic analysis to understand the past, present and future of 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 understand yet.”

Professor George Vassiliou, co-senior author of the study, formerly from 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 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.”

ENDS

Contact details:
Rachael Smith

Press Office
Wellcome Sanger Institute
Cambridge, CB10 1SA

Email: press.office@sanger.ac.uk

Publications:

Margarete A. Fabre et. al. The longitudinal dynamics and natural history of clonal haematopoiesis (2022)

Funding:

This research was funded by the Leukemia and Lymphoma Society, Rising Tide Foundation for Clinical Cancer Research, Wellcome Trust and Cancer Research UK. The SardiNIA longitudinal cohort study was supported by the National Institute of Health and the European Union’s Horizon 2020 Research and Innovation Programme.

Selected websites:

The Wellcome - MRC Cambridge Stem Cell Institute is a world-leading centre for stem cell research with a mission to transform human health through a deep understanding of normal and pathological stem cell behaviour. Bringing together biological, clinical and physical scientists operating across a range of tissue types and at multiple scales, we explore the commonalities and differences in stem cell biology in a cohesive and inter-disciplinary manner. In 2019, we relocated to a new purpose-built home on the Cambridge Biomedical Campus. Housing over 350 researchers, including a critical mass of clinician scientists, the Institute integrates with neighbouring disease-focused research institutes and also serves as a hub for the wider stem cell community in Cambridge.

The University of Cambridge

The University of Cambridge is one of the world’s top ten leading universities, with a rich history of radical thinking dating back to 1209. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence.

Cambridge research spans almost every discipline, from science, technology, engineering and medicine through to the arts, humanities and social sciences, with multi-disciplinary teams working to address major global challenges. Its researchers provide academic leadership, develop strategic partnerships and collaborate with colleagues worldwide.

The University sits at the heart of the ‘Cambridge cluster’, in which more than 5,300 knowledge-intensive firms employ more than 67,000 people and generate £18 billion in turnover. Cambridge has the highest number of patent applications per 100,000 residents in the UK. www.cam.ac.uk

EMBL’s-European Bioinformatics Institute (EMBL-EBI)
The European Bioinformatics Institute (EMBL-EBI) is a global leader in the storage, analysis and dissemination of large biological datasets. We help scientists realise the potential of big data by enhancing their ability to exploit complex information to make discoveries that benefit humankind.

We are at the forefront of computational biology research, with work spanning sequence analysis methods, multi-dimensional statistical analysis and data-driven biological discovery, from plant biology to mammalian development and disease.

We are part of EMBL and are located on the Wellcome Genome Campus, one of the world’s largest concentrations of scientific and technical expertise in genomics. www.ebi.ac.uk

The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

About Wellcome

Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, global heating and infectious diseases.

 

icon-social-share-linkedin Created with Sketch.
icon-play Created with Sketch.
icon-download Created with Sketch.