Graphic: how the twins provided a breakthrough

Identical twin sisters have led British scientists to a breakthrough in leukaemia research that promises more effective therapies with fewer harmful side-effects.

By comparing Olivia Murphy, 4, who is in remission from acute lymphoblastic leukaemia, and her healthy sister, Isabella, researchers have traced the tumour stem cells that drive the most common form of childhood cancer.

The discovery will enable doctors to screen young leukaemia patients to establish the severity of their illness and spare some the harrowing side effects of aggressive chemotherapy.

Olivia, from Bromley, southeast London, is a prime example of how hazardous this can be: although her treatment has been successful, it left her unable to fight off a chicken pox infection that blinded her in one eye.

Chemotherapy has such harsh effects on children with leukaemia that between 1 and 2 per cent die because of the drug regime, according to Philip Ancliff, the consultant who treated Olivia at Great Ormond Street Hospital in London.

The stem-cell advance, from a team led by Tariq Enver, of the University of Oxford, and Mel Greaves, of the Institute of Cancer Research in London, will also open new approaches to treating the disease more effectively.

It should allow the scientists to develop ways of targeting the stem cells that drive the blood cancer and cause relapses, so that patients can be cured. This form of the disease accounts for about 85 per cent of the 450 childhood leukaemias diagnosed in Britain each year.

The study, published in Science, could have further implications for the cancers that cause lung and colon tumours, as these are also thought to be propagated by rogue stem cells. Another application could be preventive treatment for children like Isabella who are known to be at high risk of acute lymphoblastic leukaemia, whose “pre-leukaemic” cells could be killed before they cause any damage.

Professor Enver said: “This research means that we can now test whether the treatment of acute lymphoblastic leukaemia in children can be correlated with either the disappearance or persistence of the leukaemia stem cell. Our next goal is to target both the pre-leukaemic stem cell and the cancer stem cell itself with new or existing drugs to cure leukaemia while avoiding the debilitating and often harmful side effects of current treatments.”

Professor Greaves said: “This study of a twin pair discordant for leukaemia has identified the critical stem cells that initiate the disease and maintain it in a covert state for several years. We suspect that these cells can escape conventional chemotherapy and cause relapse during or after treatment. These are the cells that dictate disease course and provide the bullseye to target with new therapies.”

The twins have been crucial to the new research, as they are genetically identical but one has developed cancer whereas the other has not. The scientists found that the girls’ blood contains genetically abnormal cells known as pre-leukaemic cells. These were formed by a mutation known as translocation, in which two genes fuse to create an abnormal new one. This random event happened in a single cell in one of the twins — it is impossible to tell which one — while they were still in the womb. As the twins shared a placenta, the original mutant’s daughter cells populated the blood of both sisters.

Analysis of Isabella’s blood suggests that about one in 1,000 of her lymphocyte blood cells is preleukaemic. About 1 per cent of these pre-leukaemic cells are also stem cells that can start and sustain the cancer.

As Isabella is still healthy, it is clear that the translocation cannot trigger leukaemia by itself. About one in 100 children has the translocation, but only one in 100 develops cancer. “The crucial question is in which cells does this start,” Professor Enver said. “What is the critical hit? Isabella gave us an opportunity almost to look back in time, to see which cells the cancer begins in.”

They did this by comparing the twins’ blood. In Olivia, but not in Isabella, some pre-leukaemic stem cells had acquired a second genetic mutation that turned them cancerous. This could have begun in a single cell, possibly because of an infection.

The discovery will help doctors to monitor Isabella, and children like her, so that further genetic damage in her pre-leukaemic stem cells is caught early. Her risk of acute lymphoblastic leukaemia is estimated at one in ten, compared with one in 10,000 among children with no family history. It will fall with every year that she remains healthy. By the time she is 14, her pre-leukaemic stem cells should have died naturally.

“Pre-leukaemic cells are still evident, so the sword of Damocles is still hanging there,” Dr Ancliff said. “Hopefully, we will see them disappear.”

The study also identifies precisely the cancerous stem cells that propagate the cancer. This should enable doctors to adjust the strength of chemotherapy to match a child’s condition. As cancer stem cells can survive conventional chemotherapy, the research could also help scientists to design drugs that kill cancers.

The fight for survival

— Leukaemia is the most common form of childhood cancer in Britain, diagnosed in up to 500 children each year

— It was first identified by doctors in 1845

— The vast majority (85 per cent) of cases are lymphoblastic leukaemia, which is particularly common among preschool children

— Survival rates have improved greatly since the advent of chemotherapy in the 1950s

— Up to 90 per cent of children with leukaemia now survive for at least four years after diagnosis. This has improved from about 50 per cent two decades ago but patients still face years of toxic treatment

— Chemotherapy can affect the white blood cells that are part of the body’s defence against deadly infections

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