Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
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.
Holleman
Amy
A
Division of Pediatric Oncology-Hematology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
Cheok
Meyling H
MH
den Boer
Monique L
ML
Yang
Wenjian
W
Veerman
Anjo J P
AJ
Kazemier
Karin M
KM
Pei
Deqing
D
Cheng
Cheng
C
Pui
Ching-Hon
CH
Relling
Mary V
MV
Janka-Schaub
Gritta E
GE
Pieters
Rob
R
Evans
William E
WE
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001215:Asparaginase / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011239:Prednisolone / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012334:RNA, Neoplasm / Q000032:analysis; D012008:Recurrence; D014750:Vincristine / Q000627:therapeutic use
D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; D014750:Vincristine; D011239:Prednisolone; D001215:Asparaginase; D003630:Daunorubicin