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Genes Linked to Failure of Leukemia Drugs in Children

By Edward R. Winstead

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Leukemia and Lymphoma

In an effort to learn why some children with leukemia do not respond to standard drugs, scientists have used genomic tools to identify a small set of genes that can be used to gauge whether a child might respond to one of four commonly used leukemia drugs.

In all, the researchers identified 124 genes that behave differently depending on whether a patient’s leukemia cells are sensitive or resistant to a drug. They focused on children who had B-lineage acute lymphoblastic leukemia (ALL).

The researchers say more studies are needed before the “genetic signatures” are ready for use in the clinic. But the findings do suggest new avenues of research into why 20 percent of children with ALL do not respond to drugs.

For instance, each of the 124 genes could be a target for new drugs that might turn a non-responsive leukemia cell into a sensitive one. Only three of the 124 genes had previously been linked to drug responsiveness for any cancer.

What distinguishes this study from other investigations of drug responsiveness was its approach, says William E. Evans of St. Jude Children’s Research Hospital in Memphis, Tennessee, who led the research. Most studies start with a few dozen genes thought to be important in influencing a patient’s response; this study made no assumptions about which genes were important.

Instead, they surveyed the 12,000 genes to see which ones might be more or less active in leukemia cells compared to normal cells. Eventually, they determined that a relatively small group of genes is associated with drug resistance and, therefore, the outcomes of treatments for children with ALL.

After determining the genetic signatures using leukemia cells and health records from patients treated at their own hospital, the researchers repeated the analysis using the cells and health records of a similar group of patients treated in the Netherlands. The results were the same.

“That’s when we realized we had something exciting—when we validated the findings in another group of patients in another country,” says Evans.

The drugs examined in the study were prednisolone, vincristine, asparaginase, and daunorubicin, and the findings appear in The New England Journal of Medicine.

Because more studies are needed, these findings do not have any immediate application in the treatment of children with ALL. The physicians expect that as their research continues and is used by others, the field will learn something that is therapeutically useful.

Holleman, A. et al. Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment. The New England Journal of Medicine 352 , 533-542 ( August 5, 2004 ).

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