Amino acid stress response genes promote L-asparaginase resistance in pediatric acute lymphoblastic leukemia
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ABSTRACT:
PROVIDER: PRJNA730281 | ENA |
REPOSITORIES: ENA
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Project description:Amino acid stress response genes promote L-asparaginase resistance in pediatric acute lymphoblastic leukemia [RNA-seq]
| PRJNA730284 | ENA
Project description:Amino acid stress response genes promote L-asparaginase resistance in pediatric acute lymphoblastic leukemia [ChIP-seq]
| PRJNA730285 | ENA
Project description:Amino acid stress response genes promote L-asparaginase resistance in pediatric acute lymphoblastic leukemia [ATAC-seq]
| PRJNA826883 | ENA
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
2006-03-07 | E-GEOD-4397 | biostudies-arrayexpress
Project description:Understanding the genomic and epigenetic mechanisms of drug resistance in pediatric acute lymphoblastic leukemia (ALL) is critical for further improving treatment. The role of transcriptomic response in conferring resistance to l-asparaginase (LASP) is poorly understood, beyond asparagine synthetase (ASNS). We defined reproducible LASP response genes in LASP resistant and sensitive ALL cells lines as well as primary leukemia samples from newly diagnosed patients. Defining ATF4 target genes in ALL cell lines using ChIP-seq revealed 25% of genes that changed expression after LASP treatment were direct targets of the ATF4 transcription factor. SLC7A11 was found to be a response gene in cell lines and patient samples as well as a direct target of ATF4. SLC7A11 was also one of only 2.4% of response genes with basal level gene expression that also correlated with LASP ex vivo resistance in primary leukemia cells. Experiments using chemical inhibition of SLC7A11 with sulfasalazine, gene overexpression, and partial gene knockout recapitulated LASP resistance or sensitivity in ALL cell lines. These findings show the importance of assessing changes in gene expression following treatment with antileukemic agent for their association with drug resistance and highlight that many response genes may not differ in their basal expression in drug resistant leukemia cells.
2022-04-15 | GSE200830 | GEO
Project description:Understanding the genomic and epigenetic mechanisms of drug resistance in pediatric acute lymphoblastic leukemia (ALL) is critical for further improving treatment. The role of transcriptomic response in conferring resistance to l-asparaginase (LASP) is poorly understood, beyond asparagine synthetase (ASNS). We defined reproducible LASP response genes in LASP resistant and sensitive ALL cells lines as well as primary leukemia samples from newly diagnosed patients. Defining ATF4 target genes in ALL cell lines using ChIP-seq revealed 25% of genes that changed expression after LASP treatment were direct targets of the ATF4 transcription factor. SLC7A11 was found to be a response gene in cell lines and patient samples as well as a direct target of ATF4. SLC7A11 was also one of only 2.4% of response genes with basal level gene expression that also correlated with LASP ex vivo resistance in primary leukemia cells. Experiments using chemical inhibition of SLC7A11 with sulfasalazine, gene overexpression, and partial gene knockout recapitulated LASP resistance or sensitivity in ALL cell lines. These findings show the importance of assessing changes in gene expression following treatment with antileukemic agent for their association with drug resistance and highlight that many response genes may not differ in their basal expression in drug resistant leukemia cells.
2022-04-15 | GSE174499 | GEO
Project description:Understanding the genomic and epigenetic mechanisms of drug resistance in pediatric acute lymphoblastic leukemia (ALL) is critical for further improving treatment. The role of transcriptomic response in conferring resistance to l-asparaginase (LASP) is poorly understood, beyond asparagine synthetase (ASNS). We defined reproducible LASP response genes in LASP resistant and sensitive ALL cells lines as well as primary leukemia samples from newly diagnosed patients. Defining ATF4 target genes in ALL cell lines using ChIP-seq revealed 25% of genes that changed expression after LASP treatment were direct targets of the ATF4 transcription factor. SLC7A11 was found to be a response gene in cell lines and patient samples as well as a direct target of ATF4. SLC7A11 was also one of only 2.4% of response genes with basal level gene expression that also correlated with LASP ex vivo resistance in primary leukemia cells. Experiments using chemical inhibition of SLC7A11 with sulfasalazine, gene overexpression, and partial gene knockout recapitulated LASP resistance or sensitivity in ALL cell lines. These findings show the importance of assessing changes in gene expression following treatment with antileukemic agent for their association with drug resistance and highlight that many response genes may not differ in their basal expression in drug resistant leukemia cells.
2022-04-15 | GSE174498 | GEO
Project description: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. This SuperSeries is composed of the SubSeries listed below.
2006-03-08 | GSE4397 | GEO
Project description:Samples of pediatric acute lymphoblastic leukemia. All samples contain at least 90% blasts. Each sample was split into two flasks, one of which was exposed to 2IU/ml of L-asparaginase. The other flask served as a control. Cells were lysed at the times indicated. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2006-01-21 | GSE4071 | GEO
Project description:Samples of pediatric acute lymphoblastic leukemia. All samples contain at least 90% blasts. Each sample was split into two flasks, one of which was exposed to 2IU/ml of L-asparaginase. The other flask served as a control. Cells were lysed at the times indicated. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Using regression correlation
2006-01-20 | E-GEOD-4071 | biostudies-arrayexpress