Currently, 20 per cent of children with ALL do not respond to the same drug therapy that cures the remaining 80 per cent. ALL afflicts 4 out of every 100 000 children worldwide. In the UK there are approximately 450 cases per year.
Drug resistance is a major cause of treatment failure, and the biochemical mechanisms responsible for de novo resistance are largely unknown. De novo resistance means that the resistance is "built into" the leukaemia cells through a particular pattern of gene expression, rather than acquired through genetic mutation during 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.
The investigators at St. Jude Children's Research Hospital, identified the specific pattern of gene expression in ALL cells linked to de novo cross-resistance to four widely used antileukemic agents, and to determine how those genes affected treatment outcome.
"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 William Evans, St. Jude's director.
"The results also give us crucial information into treatment failure that could help us design more effective treatments for the children our current treatment strategies fail to cure," he added.
The latest study was designed to assess gene expression levels in ALL cells. Researchers identified 45 genes closely linked to leukaemia 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 leukaemia 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 per cent had a five-year, relapse-free survival compared to 91 per cent 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 per cent, compared to 56 per cent 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 Cheok, 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," he said.
The report on the study that produced this new information appears in the April issue of Cancer Cell.