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
Project description:Samples of pediatric acute lymphoblastic leukemia obtained from patients at diagnosis. All samples contain at least 77% blasts. Asparaginase LC50 values were determined for each of these samples. (LC50 was determined on a different aliquot of the same sample.) Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
Project description:Samples of pediatric acute lymphoblastic leukemia obtained from patients at diagnosis. All samples contain at least 77% blasts. Asparaginase LC50 values were determined for each of these samples. (LC50 was determined on a different aliquot of the same sample.)
Project description:Samples of pediatric acute lymphoblastic leukemia obtained from patients at diagnosis. All samples contain at least 77% blasts. Asparaginase LC50 values were determined for each of these samples. (LC50 was determined on a different aliquot of the same sample.)
Project description:Samples of pediatric acute lymphoblastic leukemia obtained from patients at diagnosis. All samples contain at least 77% blasts. Asparaginase LC50 values were determined for each of these samples. (LC50 was determined on a different aliquot of the same sample.) Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Using regression correlation
Project description:Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3 inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase. To gain further insights into mechanisms of cytotoxicity of this combination, we applied unbiased mass spectrometry proteomics to CCRF-CEM cells, a human T-cell acute lymphoblastic leukemia cell line, treated with vehicle, asparaginase alone, the GSK3 inhibitor BRD0705 (which phenocopies Wnt/STOP pathway activation), or the combination of asparaginase and BRD0705.
Project description:Transcription profiling by array of human acute lymphoblastic leukemia and normal haemopoietic samples using Agilent Whole Human Genome Oligo Microarrays
