Holleman A et al. (2004) Gene-expression patterns in drug resistant acute lymphoblastic leukemia cells and response to treatment. New Engl J Med 351: 533–542

Current drug treatments fail in about 20% of children with acute lymphoblastic leukemia (ALL). Holleman and colleagues have investigated the multiple pathways governing drug resistance in their recent gene-expression profiling study.

Leukemia cells from 173 children were first tested for sensitivity in vitro to the drugs prednisolone, vincristine, asparaginase and daunorubicin. Genes that were differentially expressed in drug-resistant and drug-sensitive cells were then identified by means of an oligonucleotide microarray. Finally, gene-expression signatures associated with resistance or sensitivity to each of the four drugs were compared with treatment outcome in both the original cohort and a second cohort of 98 children.

A total of 124 genes, belonging to numerous functional groups, were differentially expressed in cells resistant or sensitive to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes) or daunorubicin (20 genes). Of these genes, 121 had not previously been linked to resistance to these drugs. Multivariate analysis indicated that expression of genes associated with drug resistance had an independent influence on outcome of treatment in both the original 173 patients and the validation cohort, who were being treated at a different center.

Holleman et al. conclude that differential expression of relatively few genes is linked with treatment response in childhood ALL, and that these genes may provide targets for improved therapy.