Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human drug sensitive and resistant ALL cells obtained at diagnosis from 174 patients

ABSTRACT: Cellular 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 (Pâ¤0.001) 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.

ORGANISM(S): Homo sapiens

SUBMITTER: William Evans

PROVIDER: E-GEOD-635 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Holleman Amy A 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

The New England journal of medicine 20040801 6

<h4>Background</h4>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.<h4>Methods</h4>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 different ...[more]

PMID: 15295046

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Project description:This SuperSeries is composed of the following subset Series: GSE4070: Clinical acute lymphoblastic leukemia samples (untreated) with known asparaginase LC50 values GSE4071: Clinical pediatric acute lymphoblastic leukemia samples after in vitro exposure to L-asparaginase GSE4072: L-asparaginase exposure in acute lymphoblastic leukemia cell lines time series Abstract: To investigate the effect of l-asparaginase on acute lymphoblastic leukemia (ALL), we used cDNA microarrays to obtain a genome-wide view of gene expression both at baseline and after in vitro exposure to l-asparaginase in cell lines and pediatric ALL samples. In 16 cell lines, a baseline gene expression pattern distinguished l-asparaginase sensitivity from resistance. However, for 28 pediatric ALL samples, no consistent baseline expression pattern was associated with sensitivity to l-asparaginase. In particular, baseline expression of asparagine synthetase (ASNS) was not predictive of response to l-asparaginase. After exposure to l-asparaginase, 5 cell lines and 10 clinical samples exhibited very similar changes in the expression of a large number of genes. However, the gene expression changes occurred more slowly in the clinical samples. These changes included a consistent increase in expression of tRNA synthetases and solute transporters and activating transcription factor and CCAAT/enhancer binding protein family members, a response similar to that observed with amino acid starvation. There was also a consistent decrease in many genes associated with proliferation. Taken together, the changes seem to reflect a consistent coordinated response to asparagine starvation in both cell lines and clinical samples. Importantly, in the clinical samples, increased expression of ASNS after l-asparaginase exposure was not associated with in vitro resistance to l-asparaginase, indicating that ASNS-independent mechanisms of in vitro l-asparaginase resistance are common in ALL. These results suggest that targeting particular genes involved in the response to amino acid starvation in ALL cells may provide a novel way to overcome l-asparaginase resistance. Refer to individual Series

Dataset Information

Transcription profiling of human drug sensitive and resistant ALL cells obtained at diagnosis from 174 patients

Publications

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

Similar Datasets

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