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Gene expression pattern predicts multiple drug resistance, treatment failure in pediatric leukemia

strategies fail to cure."

Evans is senior author of the Cancer Cell report.

The ALL cells used in the study were isolated from the bone marrow or the blood of patients with newly diagnosed disease who were being treated at St. Jude, the Dutch Childhood Oncology Group at the Sophia Children's Hospital in the Netherlands or the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia at the Children's University Hospital in Hamburg, Germany.

Using pharmacogenomics techniques to assess gene expression levels in ALL cells, researchers identified 45 genes closely linked with leukemic cells' ability to resist treatment by at least two of the most widely used antileukemic drugs. The drugs tested were prednisolone, vincristine, asparaginase and daunorubicin. The team also identified 139 genes that are closely linked to a previously unknown and unexpected type of drug resistance in which leukemic cells are resistant to asparaginase (ASP) but sensitive to vincristine (VCR). This "discordant" type of resistance (resistance to one drug and sensitivity to another) was associated with a poor response in children who had this pattern of gene expression.

Cross-resistant patients had significantly worse outcomes as a group. Among patients whose ALL cells were cross-resistant, only 53 percent had a five-year, relapse-free survival compared to 91 percent of those whose ALL cells were cross-sensitive to all the drugs.

Among patients whose ALL cells were ASP-sensitive plus VCR-resistant, the five-year, relapse-free survival rate was 93 percent, compared to 56 percent among patients whose ALL cells were VCR sensitive and ASP resistant. The genes linked to discordant resistance included many that are involved with the function of ribosomes, the cell's protein-making factories.

"This discordant resistance has not previously been described by other researchers," said Meyling H. Cheok, Ph.D., one of the postdoctoral fellows who did much of
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Contact: Carrie Strehlau
Carrie.Strehlau@stjude.org
901-495-3306
St. Jude Children's Research Hospital
18-Apr-2005


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