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Research on hairy-cell leukaemia shows the promise of new DNA-scanning technologies

by Oliver Childs | Analysis

11 June 2011

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Hairy-cell leukaemia

Scientists have found the genetic cause of hairy-cell leukaemia

The pace of change in our knowledge of cancer is astonishing.

Just 30 years ago scientists discovered the first cancer-causing DNA change. Today, scientists have catalogued countless genes that contribute to cancer, which has directly led to significant improvements in the diagnosis and treatment of the disease.

One of the best-known examples is the discovery of the BRCA genes in the 1990s.

Thanks to this work, doctors can now identify women at high risk of breast and ovarian cancer, giving them tailored advice about prevention and screening. And new drugs that target these genetic faults are currently being tested in clinical trials.

The good news is that this research has contributed to – and will continue to contribute to – the steady fall in the number of people dying from cancer.

But, more importantly, we’ve only scratched the surface when it comes to understanding how faulty genes contribute to cancer. And the buzzword of the moment – ‘genomics’ – is driving a new era in our knowledge of cancer and new insights into how to beat it.

Research into a rare form of leukaemia, published today in the New England Journal of Medicine is a glowing example of what can be achieved with the tools of the ‘genomics era’ – next-generation sequencing technologies.

Hairy-cell leukaemia

The work was carried out by scientists at the University of Perugia in Italy who were  searching for the underlying genetic causes of a rare type of chronic leukaemia called ‘hairy-cell leukaemia’, or HCL for short.

In case you’re wondering where the unusual name comes from, the abnormal blood cells in HCL have characteristic hair-like spikes on their surfaces when viewed down a microscope (you can just about make these out in the photo at the top of this post).

In spite of remarkable progress in the diagnosis and treatment of HCL in the past 50 years, scientists had failed to pinpoint any common shared genetic changes that cause the disease.

Such work had included so-called ‘genome-wide association’ or SNP studies, in which scientists scan DNA taken from thousands of people, looking for common genetic variations (or ‘markers’) associated with cancer. Like pins on a map, these markers highlight certain locations in the genome, pointing researchers towards nearby genes that might be involved in disease. But for HCL, these clues were few and far between.

In their bid to finally pinpoint common genetic changes, the Italian team decided to delve deeper into the genetic code using powerful next-generation DNA sequencing technologies.

Rather than scanning only for markers, next-generation sequencing is capable of reading every single letter of the genetic code. So, rather than sticking pins in a map, next-generation sequencing reveals the whole landscape at once.

It’s only in recent years that such work has become possible, as advances in technology make it cheaper and faster to read DNA than ever before.

To put it in perspective, the Human Genome Project took about 13 years and cost many millions of pounds to sequence the human genome. Now, a whole genome can be sequenced in a matter of weeks for a few thousand pounds. And the price is dropping all the time.

The beginning: a sick patient

The work started in March 2009, when a 47-year old man turned up at his doctor’s with symptoms of fever and pneumonia. Subsequent tests showed that he had a low number of white blood cells in his blood and an enlarged spleen, both common symptoms of HCL.

Further tests proved that he had HCL, and he was given a chemotherapy drug called pentostatin. Following 5 months of treatment his cancer cells stopped growing, his symptoms went away, and cancer cells no longer showed up in his bloodstream.

Along the way, the researchers took samples of both the man’s healthy cells and his leukaemia cells. They then used next-generation sequencing machines to read the entire DNA code of these cells.

Their aim was to compare and contrast the DNA from healthy and cancer cells to spot the genetic changes that were driving the disease.

An intriguing result

The sequencing revealed five faults that were present in the man’s cancer cells but not in his healthy ones. And one fault in particular caught the eye of the researchers.

It was in a gene called BRAF. This was intriguing because the scientists already knew that this fault – called ‘V600E’ – was involved in other cancers such as malignant melanoma and some thyroid cancers.

The researchers wanted to know more – was this just a coincidence, or could BRAF be driving the growth of HCL too?

From one patient to many patients

To find out, the team took samples from 47 other HCL patients.  They also took samples from 195 patients with other types of leukaemia or lymphoma.

Rather than using next-generation sequencing to read the entire genome blueprint in these samples, the researchers focused on the BRAF gene specifically.

Astonishingly, the same V600E fault was present in every single one of the HCL samples, but none of the samples from the patients with other types of cancer.

But when they looked at healthy cells from 10 of the HCL patients, the BRAF fault wasn’t there. This shows that they had picked up the fault during their lifetime, rather than inheriting it – suggesting it was likely to be involved in the development of the disease.

What does this work mean for patients with HCL?

This work will need to be verified in further studies, but it’s nevertheless striking and exciting that the BRAF fault was present in 100 per cent of HCL patients that the scientists tested.

But what does this mean for people with HCL, a disease that in many cases can already be successfully treated? Around 96 of every 100 people diagnosed with HCL will live for at least 10 years after they are diagnosed, making it one of the most treatable forms of leukaemia.

Firstly, it could lead to a new diagnostic tool to accurately distinguish HCL from other ‘HCL-like’ leukaemias and lymphomas, and so help decide which treatment to give patients. This is important because these diseases do not respond to the same types of chemotherapy, so patients can be spared from unnecessary treatment.

The work also suggests that patients who have not responded well to standard therapies may benefit from taking a drug that targets the BRAF fault in their HCL cells.

Last week we saw widespread media coverage of clinical trial results suggesting that the BRAF-blocking drug vemurafenib (formerly known as PLX4032) could help to treat malignant melanoma.

Although it still needs to be tested in the lab and then clinical trials, it’s possible that vemurafenib, or drugs like it, might also be effective for treating HCL too.

Wider implications – the genomic era

As well as being important for people affected by HCL, this research showcases the incredible potential of new DNA sequencing technologies to crack the cancer code.

And in the future, combining our growing understanding of the genetic faults that drive cancer with highly targeted new drugs will enable us to make even more progress in beating cancer.



Tiacci, E. et al  (2011). Mutations in Hairy-Cell Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1014209