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Whole-genome survey leads to a new classification of leukemia
By Marlene Cimons


Pediatric oncologists have long been frustrated by their inability to treat a small number of infant leukemia patients who relapse after standard chemotherapy and often die. These babies all have an aberration on chromosome 11 that doctors now think may account for the terrible prognosis.

Colors representing gene activity (red is high, blue is low) show that MLL has a distinct pattern from both ALL and AML. Each vertical column of squares represents a tumor sample. Each horizontal row of squares represents the activity of one gene. View larger.

The aberration occurs when chromosome 11 breaks off and migrates to another part of the genome. The new arrangement, or translocation, disrupts a gene on chromosome 11 called the mixed-lineage leukemia gene, or MLL.

Infants with the MLL translocation have typically been diagnosed with an aggressive form of a relatively common leukemia, acute lymphoblastic leukemia (ALL). This disease is treatable—nearly 80 percent of children with ALL respond to a regimen of a half dozen chemotherapy drugs over two years. Given the same treatment, most infants with the MLL translocation die.

Now, scientists have used DNA microarrays, or gene chips, to show that the rare and often deadly blood cancer is a genetically distinct type of leukemia. The finding may explain why infants with the translocation do not respond to current treatment and raises the possibility that in the future it can be treated with drugs that target the unique genetic characteristics of the disorder.

"It turns out that the gene expression profile of this group is very different—it's not your common ALL," says Scott A. Armstrong, of the Dana-Farber Cancer Institute in Boston. The study was published in Nature Genetics.

Stanley J. Korsmeyer, a Howard Hughes Medical Institute investigator at the Dana-Farber Cancer Institute who led the study, agrees. "The purpose of being so bold as to insist that MLL is a unique disease is to put more pressure on ourselves to rethink the therapy and test new molecular targets to see if we cannot improve upon the dismal prognosis of these infants," he says.

Armstrong and his colleagues at Dana-Farber and Harvard Medical School determined that about 1,000 genes were significantly less active in MLL cells compared to cells from ALL patients; about 200 genes were overactive in the MLL cells.

More important, the scientists discovered that cells responsible for leukemia in this group of infants are 'stuck' at an earlier stage of development than those found in other childhood leukemias. Leukemias are characterized by blood cells that have not reached full maturity.

"We had always wondered whether this was a leukemia of more immature stem cells," Korsmeyer says. "The expression profiling taught us that MLL is not just subtly different from the other infant leukemias." If the diseases are in fact profoundly different, then it makes sense that MLL patients do not respond to standard therapy for conventional ALL.

The study identified one gene in particular that distinguishes MLL from ALL and another common form of childhood leukemia, AML (acute myelogenous leukemia). The gene, called FLT3, makes an enzyme known as a tyrosine kinase, which stimulates cell growth. The gene is highly expressed in MLL and it may provoke the uncontrolled reproduction of cells in children with MLL. It is also a potential drug target.

"The gene that most distinguishes MLL from ALL or AML is FLT3, which is a tyrosine kinase," says Korsmeyer, noting that this molecule has attracted the attention of pharmaceutical companies. "A number of companies have programs on these kinases, including Novartis, who had the recent success of STI571, or Gleevec."

The US Food and Drug Administration approved Gleevec last May to treat chronic myeloid leukemia, an adult-onset form of the disease. Korsmeyer's laboratory is now trying to determine the role of FLT3 in MLL and will test the effects of potential FLT3 inhibitors.

"We already know a lot about tyrosine kinase, which is thought to be the cause of AML in 20 percent of adults," Armstrong says. He predicts that there will be many upcoming clinical trials using molecules that inhibit the enzyme in adults with AML. If these drugs prove to be successful in adults, the researchers will investigate their use in children.

The approach taken by the Dana-Farber team—using microarrays to determine how genes work in concert—is fast emerging as the tool of choice for researchers studying a wide range of cancers.

"This type of analysis is being done for every cancer you can imagine," Armstrong says. "We hope the current study affirms the idea that one can do expression profiling and use the information in the development of new drugs."

See related GNN article
»New type of leukemia identified

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Armstrong, S.A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30, 41-47 (January 2002).

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