Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown. We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution. We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in an analysis adjusting for all known clinical prognostic factors. Results were confirmed in an independent population of patients treated with the same medications. Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs.
This article appears in New England Journal of Medicine 2004. Other authors include Amy Holleman (Sophia Children’s Hospital, Rotterdam, the Netherlands), Meyling H. Cheok (St. Jude-Pharmaceutical Sciences), Monique L. den Boer (Sophia Children’s Hospital, Rotterdam, the Netherlands), Wenjian Yang (St. Jude-Pharmaceutical Sciences), Anjo J.P. Veerman (Free University Medical Center, Amsterdam), Karin M. Kazemier (Sophia Children’s Hospital, Rotterdam, the Netherlands), Deqing Pei (St. Jude-Biostatistics), Ching-Hon Pui (St. Jude-Oncology), Mary V. Relling (St. Jude-Pharmaceutical Sciences), Gritta E. Janka-Schaub (Children’s University Hospital, Hamburg, Germany), Rob Pieters (Sophia Children’s Hospital, Rotterdam, the Netherlands), and William E. Evans (St. Jude-Pharmaceutical Sciences).
Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM, Pei D, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R, Evans WE. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 351(6):533-42, 2004. PubMed Abstract