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Sequencing of matched pair samples (diagnosis and relapse) in human B-cell acute lymphoblastic leukemia cells (ALL)

ABSTRACT: The experiment focused on how B-cells respond transcriptionally to drug treatment in acute lymphocytic leukemia (ALL). We obtained B-cell samples from a patient at diagnosis (LAX7) and after the development of resistance (LAX7R) following a standard 3-week chemotherapy regimen (vincristine, dexamethasone, L-asparaginase and doxorubicin). The resistance sample possessed a KRASG12V mutation not present at diagnosis. Cells obtained from the patient were directly engrafted into NOD/SCIDγc-/- mice, and later frozen as stocks.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102301 | GEO | 2018/02/12

REPOSITORIES: GEO

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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

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Sequencing of matched pair samples (diagnosis and relapse) in human B-cell acute lymphoblastic leukemia cells (ALL)

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