[OT] Tracking Leukemia's Starting Point

[Guest guest]

Tracking Leukemia's Starting Point

By Couzin

ScienceNOW Daily News

17 January 2008

Like all cancers, childhood leukemia starts silently, and how it begins is a

perennial puzzle. Some leukemias have been tied to cancer " stem cells " that may

drive the early stages of illness and possibly induce relapses. Now researchers

in the U.K., Italy, and Japan say they've discovered a stem cell for the most

common form of childhood leukemia. Helping them were twin girls, one of whom has

the disease and one of whom is healthy.

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 . 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

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.

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