Published online 17 January 2008 | Nature | doi:10.1038/news.2008.447
Corrected online: 18 January 2008

News

Twins yield leukaemia stem cells

Pre-cancerous cells could be used to track the success of chemotherapy.

Olivia and Isabella MurphyTHE MURPHY FAMILY

Researchers have tracked down the cells at the source of the most common form of cancer in children, a disease called acute lymphoblastic leukaemia.

Now that the cells have been identified, they could be used as targets to design new therapies, or as sentinels to monitor the progression of chemotherapy.

Some cancers, including leukaemia, are thought by some to derive from a small population of cells called cancer stem cells. Although the concept has generated controversy, the hypothesis is that just a few of these cells are sufficient to generate a cancer. That means that chemotherapy and other treatments targeted at eradicating cancer must destroy nearly all these cells to be effective.

“You can get rid of most of the tumour with chemotherapy, but unless you get rid of the cancer stem cells, the cancer will grow back,” says Tariq Enver, a cancer biologist at the University of Oxford in the United Kingdom. Enver compares the process to weeding a garden: “it’s critical to get the roots.”

Enver and his colleagues dug down to the roots of acute lymphoblastic leukaemia by studying a set of young twins. One of the twins, Isabella Murphy, is healthy; the other, Olivia, was diagnosed with leukaemia when she was two years old.

The twins are identical and developed within a shared membrane surrounding both fetuses. This allowed some exchange of cells between Olivia and Isabella — possibly including early ‘pre-leukaemic’ cells growing in Olivia that would later give rise to her disease.

Back in time

Patients with acute lymphoblastic leukaemia often have a chromosomal abnormality that occurs spontaneously during development and causes two genes to fuse together. Olivia's cells have this abnormality.

Enver and his colleagues isolated a subset of the cells containing this gene fusion and transplanted a small number into mice with deficient immune systems. The mice then developed a leukaemia-like illness, suggesting that this subset of cells might be leukaemia stem cells1.

The researchers then wanted to trace the cancer-cell lineage back even further, to before it became malignant. For this, they turned to Isabella. “The healthy twin gives you a way of looking back in time to where things started,” says Enver. "There was the possibility that she might have pre-leukaemic cells."

They found a small population of cells in Isabella that also contained the gene fusion. Several features of these cells suggested that they were immature predecessors of the cancer stem cells found in Olivia. Enver has termed these cells ‘pre-leukaemic stem cells’.

For Isabella, the presence of the cells slightly increases the chance that she will develop leukaemia. Enver estimates the odds at around 10%, but notes that this estimate is little more than a guess. Presence of the gene fusion is only one in a series of mutations that must occur for leukaemia to develop. Isabella already undergoes regular testing for leukaemia, just in case.

Lurking threats

Enver does not recommend testing for pre-leukaemia cells as a way to screen all children for the disease. “The frequency of transition from pre-leukaemia to leukaemia is low,” he says. “I think that could end up just causing a lot of anxiety without a lot of benefit.”

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Nevertheless, the research provides a rare and important glimpse into the very early stages of cancer, says Peter Dirks, a cancer biologist at the Hospital for Sick Children in Toronto, Canada. "It's quite extraordinary," says Dirks. "It's one of the first opportunities to study the evolution of a cancer."

Enver speculates that the presence of leukaemia stem cells or pre-leukaemia stem cells could explain the difference between early and late relapses after periods of remission in different patients. If the chemotherapy leaves behind any leukaemia stem cells, those cells simply need to reproliferate to cause a relapse. If it wipes out leukaemia stem cells but leaves some pre-leukaemia stem cells, these would need to accumulate additional mutations before triggering cancer — a process that could take considerably longer. “The threat may lurk at two levels,” Enver says.

If that speculation holds true, such cells could be monitored to determine how successful a bout of chemotherapy has been. 

Corrected:

An earlier version of this story incorrectly stated that the twins were fraternal; they are identical.
  • References

    1. Hong, D. et al. Science 319, 336-339 (2008). | Article |
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