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Previous Volume 351:533-542 August 5, 2004 Number 6 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Winick, N. J. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background 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.

Methods 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.

Results 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 a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.

Conclusions Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.

Source Information

From the Division of Pediatric Oncology–Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands (A.H., M.L.B., K.M.K., R.P.); the Departments of Pharmaceutical Sciences (M.H.C., W.Y., M.V.R., W.E.E.), Hematology–Oncology (C.-H.P.), and Biostatistics (D.P., C.C.), St. Jude Children's Research Hospital, Memphis, Tenn.; the Pharmacogenetics of Anticancer Agents Research Group in the Pharmacogenetics Research Network, Memphis, Tenn. (W.Y., C.-H.P., M.V.R., W.E.E.); University of Tennessee Colleges of Pharmacy and Medicine, Memphis (C.-H.P., M.V.R., W.E.E.); Free University Medical Center, Department of Pediatric Hematology–Oncology, Amsterdam (A.J.P.V.); and the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Department of Hematology–Oncology, Children's University Hospital, Hamburg, Germany (G.E.J.-S.).

Ms. Holleman and Dr. Cheok contributed equally to the article, and Drs. Pieters and Evans contributed equally to the article.

Address reprint requests to Dr. Evans at St. Jude Children's Research Hospital, Department of Pharmaceutical Sciences, 332 N. Lauderdale St., Memphis, TN 38105, or at william.evans{at}stjude.org.

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