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Roles of activating transcription factor 4 in the murine response to asparaginase in liver.

ABSTRACT: In liver, the anti-leukemic agent asparaginase (ASNase) increases phosphorylation of eukaryotic initiation factor 2 by general control nonderepressible 2 (GCN2) kinase. This event promotes gene-specific translation of activating transcription factor 4 (ATF4) which alters gene expression in response to amino acid depletion. The objective of this study was to investigate the role of GCN2 versus ATF4 in controlling the global transcriptome to ASNase in liver. We compared global gene expression patterns in livers from wildtype,Gcn2-/-, andAtf4-/-mice (all on C57BL/6J background) treated with ASNase or phosphate buffered saline (PBS) excipient. These analyses revealed that ATF4 controls a hepatic gene expression profile that partially overlaps with GCN2 both basally and following amino acid depletion by ASNase.

ORGANISM(S): Mus musculus

PROVIDER: GSE92364 | GEO | 2017/04/30

SECONDARY ACCESSION(S): PRJNA357300

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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Roles of activating transcription factor 4 in the murine response to asparaginase in liver.

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