Public Release: 

Leukemia-associated mutations almost inevitable as we age

Researchers estimate that 7 in 10 over 90-year-olds have early leukemia cells

Wellcome Trust Sanger Institute

It is almost inevitable that we will develop genetic mutations associated with leukaemia as we age, according to research published today in Cell Reports. Based on a study of 4219 people without any evidence of blood cancer, scientists estimate that up to 20 per cent of people aged 50-60 and more than 70 per cent of people over 90 have blood cells with the same gene changes as found in leukaemia.

Scientists investigating the earliest stages of cancer development used an exquisitely sensitive sequencing method capable of detecting DNA mutations present in as few as 1.6 per cent of blood cells, to analyse 15 locations in the genome, which are known to be altered in leukaemia. By comparing their findings with other research conducted with a lower degree of sensitivity over whole exomes, the scientists were able to conclude that the incidence of pre-leukaemic cells in the general population is much higher than previously thought and increases dramatically with age.

"Leukaemia results from the gradual accumulation of DNA mutations in blood stem cells, in a process that can take decades," explains Dr Thomas McKerrell, joint first author from the Wellcome Trust Sanger Institute. "Over time, the probability of these cells acquiring mutations rises. What surprised us was that we found these mutations in such a large proportion of elderly people. This study helps us understand how aging can lead to leukaemia, even though the great majority of people will not live long enough to accumulate all the mutations required to develop the disease."

The pre-leukaemic mutations studied appear to give a growth advantage to the cells carrying them and this starts a process in which cells with these mutations dominate blood making. As they increase in number, the likelihood that one or more of them will acquire more mutations becomes greater, something that could eventually lead to leukaemia and leukaemia-like disorders. Interestingly, the study found that mutations affecting two particular genes, SF3B1 and SRSF2, appeared exclusively in people aged 70, suggesting that these mutations only give a growth benefit later in life, when there is less competition. This finding explains why myelodysplastic syndromes, a group of leukaemia-like conditions associated with these genes, appear almost exclusively in the elderly.

None of the 4219 people studied were found to have a mutation in NPM1, the most common acute leukaemia gene mutated in up to 40 per cent of cases. This unexpected result suggests that mutations in NPM1 behave as gatekeepers for this cancer; once a mutation in this gene occurs in a cell with particular previously accumulated pre-leukaemic mutations, the disease progresses rapidly to become leukaemia.

"The significance of mutations in this gene is astonishingly clear from these results: it simply doesn't exist where there is no leukaemia," says Dr Naomi Park, joint first author from the Sanger Institute. "When it is mutated in the appropriate cell, the floodgates open and leukemia is then very likely to develop. This fits with studies we've conducted in the past in which we found that the gene primes blood stem cells for leukaemic transformation."

Leukaemia serves as a useful model for research into the origins of cancer because blood samples are much easier to obtain than tissue samples. Each cancer begins with a single mutation in just one cell; this research allows scientists to look at how these first mutated cells accumulate to form cancer.

"Ultra-deep sequencing has allowed us to see the very beginnings of cancer," says Dr George Vassiliou, senior author from the Sanger Institute and Cambridge University Hospitals NHS Trust. "These mutations will be harmless for the majority of people but for a few unlucky carriers they will take the body on a journey towards leukaemia. We are now beginning to understand the major landmarks on that journey."

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Notes to Editors

Publication details

McKerrell T, Park N, et al. (2015). Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Reports. DOI: 10.1016/j.celrep.2015.02.005

Funding

This project was funded by a Wellcome Trust Clinician Scientist Fellowship (TM) and by the Wellcome Trust Sanger Institute (grant number WT098051). GV is funded by a Wellcome Trust Senior Fellowship in Clinical Science (Wt095663MA) and work in his laboratory is also funded by Leukaemia Lymphoma Research and the Kay Kendal Leukaemia Fund. IV is funded by Spanish Ministerio de Economía y Competitividad subprogram Ramón y Cajal.

Participating Centres

Wellcome Trust Sanger Institute, Universidad de Cantabria, University of Cambridge, NHS Blood and Transplant, Institute for Social and Economic Research at the University of Essex, Cambridge University Hospitals NHS Trust, Technische Universität München and the German Cancer Research Center.

Selected Websites

Universidad de Cantabria

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 90 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of one of the world's largest technology clusters. The 'Cambridge Phenomenon' has created 1,500 hi-tech companies, 12 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation.

http://www.cam.ac.uk/

NHS Blood and Transplant (NHSBT) is a joint England and Wales Special Health Authority. Its remit includes the provision of a reliable, efficient supply of blood and associated services to the NHS in England and North Wales. It is also the organ donor organisation for the UK and is responsible for matching and allocating donated organs.

http://www.nhsbt.nhs.uk/

Understanding Society is an initiative by the Economic and Social Research Council, with scientific leadership by the Institute for Social and Economic Research, University of Essex, and survey delivery by the National Centre for Social Research and TNS BRMB.

https://www.understandingsociety.ac.uk/

Cambridge University Hospitals is one of the largest and best known trusts in the country. As the local hospital for our community we deliver care through Addenbrooke's and the Rosie hospitals. We are also a leading national centre for specialist treatment, a government-designated comprehensive biomedical research centre, one of only five academic health science centres in the UK and a university teaching hospital with a worldwide reputation. Building on these different elements, our vision is to be one of the best academic healthcare organisations in the world.

http://www.cuh.org.uk/

Technische Universität München (TUM) is one of Europe's leading research universities, with around 500 professors, 10,000 academic and non-academic staff, and more than 37,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel and Carl von Linde have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, it regularly places among the best universities in Germany.

http://www.tum.de/en/homepage/

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is the largest biomedical research institute in Germany and a member of the Helmholtz Association of National Research Centers. In over 90 divisions and research groups, more than 3000 employees, of which more than 1000 are scientists, are investigating the mechanisms of cancer, are identifying cancer risk factors and are trying to find strategies to prevent people from getting cancer. They are developing novel approaches to make tumour diagnosis more precise and treatment of cancer patients more successful.

http://www.dkfz.de/en/index.html

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

http://www.sanger.ac.uk

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

http://www.wellcome.ac.uk

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