Our cells are dividing all the time – replacing worn-out cells and healing injuries. But cell division can be a tricky business – every time a cell divides, each one of its 46 chromosomes, and the DNA they are made of, must be copied perfectly. Time and time again the cells in our bodies divide without a single hitch, largely due to the many checks and balances that are in place to prevent problems.
Telomeres – miniscule structures that cap and protect the ends of each of a cell’s chromosomes– are one such safety check. Each time a cell divides the telomeres get a little bit shorter, limiting the cell’s natural lifespan and preventing runaway cell division – the hallmark of cancer.
Now new research published today in the journal Blood reveals how cells that bypass this safety check might be able to trigger the development of leukaemia, and potentially many other types of cancer. The researchers believe it could one day lead to a blood test to predict how fast leukaemia will progress.
Listen to lead researcher Dr Duncan Baird talking about his discovery:
The long and short of it
Scientists have suspected for some time that faulty telomeres may be a driving force in many types of cancer. But most research has focused on a vital protein called telomerase – which researchers have shown is responsible for building and maintaining telomeres – and which is switched on in around 8 out of 10 cancers. Crucially, it seems that this overactive telomerase enables cancer cells to carry on multiplying.
But research being carried out by Dr Duncan Baird and his colleagues at Cardiff University suggests that, during the earliest stages of leukaemia, telomerase is not actually active enough to maintain the telomeres. So they become shorter and shorter, to the extent that they no longer protect the chromosomes. But how does this drive the development of cancer?
Along with telomeres and telomerase, our cells contain sophisticated sensors that can recognise the ends of strands of DNA and glue them back together. This protects us from cancer by repairing any nicks or breaks that occur. But telomeres mask the ends of chromosomes, preventing the cell from accidentally gluing them together, which would cause serious problems.
Baird and his team found that in early leukaemia cells, where telomerase isn’t sufficiently active, the ends of the chromosomes become exposed. And, as you might expect, bits of the chromosomes break off and reattach elsewhere, causing large sections of the DNA to become fused, deleted or otherwise faulty.
Normally, cells with such damaged chromosomes would die. But these ones don’t – they go on to multiply out of control, resulting in leukaemia.
Baird and his team believe there is a two-step process at work – first, telomerase gets shut down, so the telomeres get shorter and chromosomes fuse together. Then telomerase gets switched back on, so the faulty cells become ‘immortal’ and keep on multiplying.
What they did
To make their discovery, the scientists took samples from 41 patients with varying stages of chronic lymphocytic leukaemia (CLL), a form of leukaemia which affects lymphocytes – a type of white blood cell. The team used a pioneering new technology, known as Single Telomere Length Analysis (STELA), to measure the length of individual telomeres of chromosomes in cancer cells.
By comparing the telomere length of the CLL patients to that of six healthy people who didn’t have leukaemia, the researchers found that the condition tended to advance more quickly in patients whose cancer cells had the shortest telomeres.
What’s more, when the researchers compared cancer cells from patients who had the most severe cases of leukaemia to cells that had been forced to divide out of control in the lab, they found it was almost impossible to tell the two apart. Both had similar genetic problems caused by the chromosomes sticking together, suggesting a link between the progression of the disease and uncontrolled cell division eroding the telomeres until they become so short the chromosomes begin to fuse.
These remarkable results build on previous research involving mice and human cells grown in the lab, which pinpointed the critical length at which telomeres lose their protective capabilities, making chromosomes prone to sticking together.
Finding out whether there is a direct link between telomere length and how fast leukaemia will progresses will require further research with larger groups of patients. But it’s an exciting prospect nonetheless, because it could potentially lead to a blood test for monitoring how fast leukaemia is progressing.
This would help doctors decide on the most appropriate treatment option for individual patients. It could also open the door for new methods of diagnosing and treating the disease.
In this study, funded by Cancer Research UK and Leukaemia & Lymphoma Research, Dr Baird’s team are the first to directly measure telomere length in human leukaemia patients and show that shortened telomeres – and the resulting ‘sticky’ chromosomes – could be driving the progression of leukaemia in these patients.
They’re now looking at whether chromosome fusion also plays a role in the progression of other types of cancer, such as bowel cancer. If it does, it could be a step towards developing new treatments or tests for a wide variety of different cancers.
Ailsa Taylor, Science Press Officer at Cancer Research UK
Lin, T. et al (2010). Telomere dysfunction and fusion during the progression of chronic lymphocytic leukaemia: evidence for a telomere crisis Blood DOI: 10.1182/blood-2010-02-272104
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