http://sciencenow.sciencemag.org/cgi/content/full/2008/117/5

Double help.
Twins Olivia (left) and Isabella helped scientists decipher how the leukemia Olivia suffers from started.

Credit: Courtesy of the Murphy family

Tracking Leukemia's Starting Point

By Jennifer Couzin
ScienceNOW Daily News
17 January 2008

A barrage of mutations sets the stage for acute lymphoblastic leukemia (ALL). In about a quarter of childhood ALL patients, the genetic alteration that puts cells on the road to cancer is the fusion of the genes TEL and AML1. Earlier studies of children with leukemia found that blood samples taken at birth had the fusion, suggesting that it occurs in utero. But the sequence of events leading to ALL, and whether "preleukemic" stem cells existed, wasn't known.

Tariq Enver, a stem cell biologist at the University of Oxford in the U.K., and his colleagues set out to find these stem cells. They injected different combinations of TEL-AML1-positive leukemia cells from ALL patients into immunodeficient mice. Cells that, when injected in relatively small numbers, could self-renew and establish leukemia in an animal--and do the same when transplanted from that animal into a second--would be considered cancer stem cells. After several tries, the researchers found a subset of cells that qualified.

Were these cells present before leukemia struck? To find out, the team turned to young identical twin girls, Olivia and Isabella Murphy. Olivia had ALL, but the team was most interested in Isabella, who wasn't sick. Because the twins had shared a placenta and a blood supply in utero, studying Isabella's blood could offer a snapshot of what Olivia's blood looked like before she got sick. In Isabella's blood, the researchers found a tiny number of preleukemic stem cells--about 0.002% of all cells drawn--and some of those had the TEL-AML1 gene fusion. These were the same type of cell that had established leukemia in the mice, although they lacked all the abnormal gene mutations of a true leukemic cell. Still, the cells in Isabella didn't show up in other healthy children, suggesting they might be a first step on the road to leukemia but needed additional genetic mutations before disease became inevitable. Over 18 months of observation of Isabella, this cell population didn't progress to leukemia. The scientists theorize that the preleukemic stem cells had passed from one girl to the other in utero. Olivia had then sustained additional genetic hits and developed ALL.

Finally, the researchers report in the 18 January issue of Science, they recreated Isabella's preleukemic stem cells by inserting a TEL-AML1 fusion gene into cord blood stem cells with the same surface markers as those that were seen in Isabella. When these cells were injected into mice, the animals developed a form of preleukemia but didn't progress to cancer. "What does it take to get that to turn into leukemia?" asks Enver. No one knows the answer.

A preleukemic stem cell "had never really been identified," says Carol Stocking, a cancer biologist at the Heinrich Pette Institute in Hamburg, Germany, who's now convinced that it has. Still, there remains much controversy about cancer stem cells generally, including how important they'll be for treatment, says Charles Mullighan, a leukemia researcher at St. Jude Children's Research Hospital in Memphis, Tennessee. But showing that this population of cells "persists over time [and is] not present in normal individuals ... is an important first step" in understanding how ALL starts, he says.

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