New study discovers genetic changes linked to leukaemia in children with Down’s syndrome | University of Oxford

New study discovers genetic changes linked to leukaemia in children with Down’s syndrome

11 July 2019

Researchers at the University of Oxford, in collaboration with colleagues from Hannover Medical School and Martin-Luther-University Halle-Wittenberg, have discovered the specific gene mutations that are required for the development of leukaemia in children with Down’s syndrome. Children with Down’s syndrome have a 150-fold increased risk of myeloid leukaemia, and while some of the genetic causes of this have been previously established, this is the first study to identify a wide range of mutations and how they functionally interact to lead to leukaemia. The study was published today in the journal Cancer Cell.

‘We already knew that 30% of babies born with Down’s syndrome have acquired a change in a gene called GATA1 in their blood cells. This is not an inherited genetic change, but one that occurs and will remain only in the baby’s blood cells,” says study author Professor Paresh Vyas, from the MRC Weatherall Institute of Molecular Medicine at the Radcliffe Department of Medicine, University of Oxford. “The abnormality in the GATA1 gene can be detected by a simple blood test at birth. Babies with an altered GATA1 gene have a predisposition to develop leukaemia, and we often refer to this as ‘myeloid preleukaemia’.’

Of the 30% of children with Down’s syndrome who are found to have ‘myeloid preleukaemia’, only 10% of those will go on to develop myeloid leukaemia (3% of all children with Down’s syndrome). Until now, it was not understood why only some children with the GATA1 mutation were progressing to full leukaemia, while others were not.

‘90% of babies with Down’s syndrome do not go on to develop leukaemia. But until now, we did not fully understand why some babies did develop leukaemia,’ says Vyas, who is also a group leader at the MRC Molecular Haematology Unit. ‘To answer this question, we carefully characterised the mutations in genes required for leukaemia to develop. We found that additional genetic changes are required in the altered GATA1 blood cells, and these additional changes transform the preleukaemic blood cells into leukaemic blood cells.’ In total, 43 different altered genes were found.

The discovery of which specific genetic changes are required for leukaemia to develop has practical implications. While children with Down’s syndrome are currently tested at birth for the GATA1 mutation, it may now become possible in the future to test for the additional mutations too. ‘This would mean that we could identify the 10% of children who will develop leukaemia more quickly and easily, and importantly reassure 90% of families whose children will not develop leukaemia,’ says Vyas. ‘The identification of these genetic changes may also mean we can develop and test new treatments specifically targeting the genetic changes we now know are required by the leukaemia – and so develop more targeted treatments with less side effects.’

Current treatments for Down’s syndrome children with leukaemia are already highly successful, and off the back of this research, another possible drug treatment has come to light. The drug Ruxolitinib, which is currently used to treat some blood conditions, could potentially be used to treat some of the specific genetic mutations found in the study. Clinical trials of the drug are a possibility for the future.

‘The recent identification of a group of genes linked to leukaemia in children with Down’s syndrome is an important first step towards developing early diagnostic tests and identifying effective treatments to help these patients,’ says Dr Mariana Delfino-Machin, Programme Manager at the Medical Research Council (MRC). ‘The MRC is proud to support the research undertaken at the MRC Molecular Haematology Unit, of which this early-stage study is a great example.’

For a copy of the paper or interviews with the researchers, contact gen.juillet@admin.ox.ac.uk or 01865 280534

Notes for editors

Full citation: Mechanisms Of Progression Of Myeloid Preleukemia To Transformed Myeloid Leukemia In Children With Down Syndrome. Cancer Cell, 11 July 2019.

This research was principally funded by the charities Bloodwise and Children with Cancer UK, as well as by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC).

About the MRC Weatherall Institute of Molecular Medicine
The MRC Weatherall Institute of Molecular Medicine (MRC WIMM) was founded in 1989 by Sir David Weatherall, and was the first institute of its kind in the UK to link basic research in molecular and cell biology with clinical research. The MRC WIMM is a strategic partnership between the Medical Research Council and the University of Oxford. The institute brings together over 500 researchers, staff and students now focusing on five research areas: rare genetic diseases, haematology, immunology and infection, stem cell and developmental biology, and cancer biology. The MRC Molecular Haematology Unit is based at the MRC WIMM. www.imm.ox.ac.uk

About the Radcliffe Department of Medicine
The Radcliffe Department of Medicine is one of the two main departments of medicine at the University of Oxford, and aims to tackle some of the world’s biggest health challenges by integrating innovative basic biology with cutting edge clinical research. The RDM has internationally renowned programmes in a range of areas including cardiovascular sciences, diabetes and endocrinology, immunology, haematology and pathology. www.rdm.ox.ac.uk

About Oxford University
Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the third year running, and at the heart of this success is our ground-breaking research and innovation.

Oxford is world-famous for research excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research sparks imaginative and inventive insights and solutions.

Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 170 new companies since 1988. Over a third of these companies have been created in the past three years. www.ox.ac.uk

About the National Institute for Health Research (NIHR)
The National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) is based at the Oxford University Hospitals NHS Foundation Trust and run in partnership with the University of Oxford. 
The NIHR is the nation's largest funder of health and care research. The NIHR:

  •  Funds, supports and delivers high quality research that benefits the NHS, public health and social care
  •  Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
  •  Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
  •  Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
  •  Partners with other public funders, charities and industry to maximise the value of research to patients and the economy
  • The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR commissions applied health research to benefit the poorest people in low- and middle-income countries, using Official Development Assistance funding.