Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients, and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting cross-resistance to prednisolone, vincristine, asparaginase and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37%13% 5-year DFS).
Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia.
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View SamplesCellular drug resistance is associated with an unfavorable prognosis in pediatric acute lymphoblastic leukemia (ALL). To identify genes conferring resistance to antileukemic agents, we analyzed the expression of >12,700 genes in sensitive and resistant ALL cells obtained at diagnosis from 174 patients. This revealed 42, 59, 54 and 22 genes (P0.001) that were differentially expressed in B-lineage ALL that was sensitive versus resistant to prednisolone, vincristine, asparaginase or daunorubicin, respectively, with prediction accuracies of 71-76%. Notably, 149 of the discriminating genes have not been previously associated with resistance to these anticancer agents. These included carbohydrate-metabolism and transcription-associated genes for prednisolone, cytoskeleton and extracellular matrix genes for vincristine, ribosomal protein and translation-associated genes for asparaginase, and RAS signaling and nucleosome remodeling complex genes for daunorubicin. The identification of novel genomic determinants of cellular drug resistance provides new insights for overcoming drug resistance in acute lymphoblastic leukemia.
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
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View Samplesprimary ALL cells (B- and T-lineage) sensitive to daunorubicinby the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
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View Samplesprimary ALL cells (B- and T-lineage) sensitive to vincristine by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samplesprimary ALL cells (B-lineage) sensitive to daunorubicin by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samplesprimary ALL cells (B- and T-lineage) sensitive to L-asparaginase by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samplesprimary ALL cells (B-lineage) sensitive to vincristine by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samplesprimary ALL cells (B-lineage) sensitive to L-asparaginase by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samplesprimary ALL cells (B- and T-lineage) sensitive to prednisolone by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samplesprimary ALL cells (B- and T-lineage) resistant to L-asparaginase by the MTT in vitro sensitivity assay
Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.
No sample metadata fields
View Samples