1: N Engl J Med.  2004 Aug 5;351(6):533-42.

Comment in:
    N Engl J Med. 2004 Aug 5;351(6):601-3.

Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and
response to treatment.

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.

Division of Pediatric Oncology-Hematology, Erasmus University Medical Center,
Sophia Children's Hospital, Rotterdam, The Netherlands.

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.

Copyright 2004 Massachusetts Medical Society