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The discovery of a specific pattern of gene expression linked to multiple-drug resistance of leukemic cells is giving researchers important new insights into why standard therapies fail to cure some children with acute lymphoblastic leukemia (ALL). This finding could lead to the development of new drugs that would overcome that resistance, according to St. Jude investigators.
This new finding helps explain why about 20 percent of children with ALL are not cured with the same drug therapy that cures the remaining 80 percent of children with this disease.
The findings are important because drug resistance is a major cause of treatment failure, and the biochemical mechanisms responsible for de novo resistance are largely unknown. De novo resistance is “built into” the leukemic cells through a particular pattern of gene expression, rather than acquired through the mutation of genes during the course of treatment. Cross-resistance to multiple drugs suggests a poor prognosis and likely involves biochemical mechanisms that are different from those linked to single-drug resistance, according to the researchers.
“The identification of a particular genetic expression pattern linked to cross-resistance takes us a significant step forward in understanding why treatment fails to cure certain children who initially looked like good candidates for standard chemotherapy,” said Hospital Director William Evans, PharmD, a member of Pharmaceutical Sciences. Evans is senior author of a report on these findings that appears in the April issue of the journal Cancer Cell.
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 and 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, the researchers identified 45 genes closely linked with the ability of leukemic cells to resist treatment with two or more of the four most widely used antileukemic drugs: prednisolone, vincristine (VCR), asparaginase (ASP) 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 ASP but sensitive to 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.
Only 53 percent of cross-resistant patients had a five-year, relapse-free survival, compared to 91 percent among those whose ALL cells were cross-sensitive to all the drugs.
Among patients whose ALL cells were ASP-sensitive and 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 protein-making factories in cells.
“This discordant resistance has not previously been described by other researchers,” said Meyling Cheok, PhD, one of the postdoctoral fellows who did much of the work on this project. “The fact that it is associated with genes involved with protein synthesis gives us an important clue to the basis of this type of drug resistance.”
Last update: May 2005