Leukaemia caused by chromosome catastrophe

Researchers have found that people born with a rare abnormality of their chromosomes have a 2,700-fold increased risk of a rare childhood leukaemia. In this abnormality, two specific chromosomes are fused together but become prone to catastrophic shattering.

Acute lymphoblastic leukaemia, or ALL, is the most common childhood cancer. Scientists previously found that a small subset of ALL patients have repeated sections of chromosome 21 in the genomes of their leukaemia cells. This form of ALL – iAMP21 ALL – requires more intensive treatment than many other types of ALL. The scientists used modern DNA analysis methods to reconstruct the sequence of genetic events that lead to iAMP21 ALL.

The team noticed that some patients with iAMP21 ALL were born with an abnormality in which chromosome 15 and chromosome 21 are fused together. The researchers wanted to discover if this type of fusion (known as a Robertsonian translocation) was connected with this rare form of ALL. They found that the joining of the two chromosomes increases a person's risk of developing the rare iAMP21 form of ALL by 2,700 fold.

“Advances in treatment are improving patients' outcomes, but iAMP21 ALL patients require more intensive chemotherapy than other leukaemia patients,” says Professor Christine Harrison, co-lead author from Newcastle University. “Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL.”

“We have been able to map the roads the cells follow in their transition from a normal genome to a leukaemia genome.”

The team developed new insights for analysing genome data that can reveal the sequence of complicated genetic changes that cause a healthy cell to become cancerous. They can now take a cancer cell at one point in time and deduce the relative timing and patterns of mutational events that occurred in that cell's life history.

The team sequenced nine samples from iAMP21 ALL patients, four with the rare Robertsonian translocation event and five that occurred in the general population. They found that for the four patients with the Robertsonian translocation, the cancer was initiated by a catastrophic genetic event known as chromothripsis. This event shatters a chromosome – in this case the joined chromosomes 15 and 21 – and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order. In the five other patients, the cancer was initiated by two copies of chromosome 21 being fused together, head to head, usually followed by chromothripsis.

“This is a remarkable cancer – for patients with iAMP 21 ALL we see the same part of the genome struck by massive chromosomal rearrangement,” says Yilong Li, a first author from the Wellcome Trust Sanger Institute. “The method we've developed can now be used to investigate genetic changes in all cancer types.”

The team found a consistent sequence of genetic events across the patients studied. Although the events at first sight seem random and chaotic, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimised to drive leukaemia.

The team will now use this method to decipher the genetic events that underlie many different cancer types.

“What is striking about our findings is that this type of leukaemia could develop incredibly quickly – potentially in just a few rounds of cell division,” says Dr Peter Campbell, co-lead author from the Wellcome Trust Sanger Institute. “We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”

Notes to Editors

Publication Details

Li Y, Schwab C, Ryan S, et al (2014) 'Constitutional and somatic genomic rearrangements coherently restructure chromosome 21 in acute lymphoblastic leukaemia'. Nature

Advanced online publication in Nature on 23 March, 2014.

DOI: 10.1038/nature13115

Funding

This work was supported by the Wellcome Trust, Leukaemia and Lymphoma Research Specialist Programme, Research Foundation – Flanders (FWO) and the European Research Council.

Participating Centres

A full list of participating centres appears on the Nature website.

Selected Websites

Newcastle University is a Russell Group University. We rank in the top 20 UK universities in The Sunday Times 2013 University Guide. Amongst our peers Newcastle is: fifth in the UK for graduates into jobs (HESA 2011-12), 10th in the UK for student satisfaction and eighth in the UK for Medical research power and in the UK's top 12 for research power in Science and Engineering. 95 per cent of our students are in a job or further training within six months of graduating. We have a world-class reputation for research excellence and are spearheading three major societal challenges that have a significant impact on global society. These themes are: Ageing and Health, Sustainability, and Social Renewal. Newcastle University is the first UK university to establish a fully owned international branch campus for medicine at its NUMed Campus in Malaysia, which opened in 2011. Our International students put Newcastle University in world's top 12 (ISB 2011).

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Leukaemia & Lymphoma Research is a leading UK charity dedicated to improving the lives of patients with all types of blood cancer, including leukaemia, lymphoma and myeloma. Its life-saving work is focused on finding causes, improving diagnosis and treatments, and running groundbreaking clinical trials for all blood cancer patients.

The charity champions patients' needs by influencing relevant policy and decision makers. Its communities give blood cancer patients and their families a place where they can find support and information and share their journey with other people who can relate to what they are going through. Around 30,000 people of all ages, from children to adults, are diagnosed with blood cancer every year in the UK.

http://www.beatingbloodcancers.org.uk

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.

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