Mutual antagonism between glucocorticoid and canonical Wnt signaling pathways impacts steroid resistance in acute lymphoblastic leukemia [RNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE215187 | GEO | 2023/06/06
REPOSITORIES: GEO
Similar Datasets
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. In this work (which is a follow-up of our recent study- Bergeron et al. Leukemia 2022), we uncovered the genomic mechanism linking disruptions to the Wnt repressor gene TLE1 with glucocorticoid (GC) drug resistance in acute lymphoblastic leukemia. In this process we uncovered extensive crosstalk and mutual antagonism between GC signaling and canonical Wnt signaling in ALL cells at the DNA sequence, transcriptome and proteome levels.
2023-06-06 | GSE215186 | GEO
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.
2022-08-25 | GSE176278 | GEO
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.
2022-08-25 | GSE175483 | GEO
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.
2022-08-25 | GSE175482 | GEO
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.
2022-08-25 | GSE175481 | GEO
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.
2022-08-25 | GSE190884 | GEO
Project description:Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of acute lymphoblastic leukemia (ALL). Although overall survival rates of childhood ALL have improved, resistance to antileukemic agents remains a major clinical concern. In particular, resistance to GCs is predictive of ALL relapse and poor clinical outcome, and it therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes and transcriptional signatures implicated in ALL GC resistance, there remains an insufficient understanding of the impact of glucocorticoid response element (GRE) alterations in GC resistance. To therefore better understand the role of gene regulatory alterations in GC resistance, we comprehensively mapped the GC gene regulatory network in two ALL cell lines using orthogonal functional genomic assays and identified tens of thousands of GREs in the ALL genome. A closer examination revealed binding profiles that were consistent with the long-range flexible billboard model of gene regulation. GCs also induced the formation of over 250 super-enhancers, and these GC-responsive super-enhancers control the expression of genes mediating GC resistance. By further integrating our results with genetic and epigenetic data in primary ALL cells from patient cohorts at St. Jude, we identified 45 DNA sequence variants associated with ex vivo GC resistance that map to GREs and validated an associated variant within the TLE1 gene locus. We also uncovered that 1929 accessible chromatin sites associated with ex vivo GC resistance were significantly enriched at GREs. A CRISPR interference screen of these elements validated their effects on GC resistance. Overall, these data suggest that GCs initiate pervasive, genome-wide effects on the leukemia epigenome and transcriptome, while genetic and epigenetic alterations to GREs are mechanisms contributing to GC resistance in childhood ALL.
2022-08-25 | GSE188713 | GEO
Project description:Drug resistance remains a major obstacle to successful cancer treatment. Here we use a novel approach to identify rapamycin as a glucocorticoid resistance reversal agent. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in Acute Lymphoblastic Leukemia (ALL) cells. The screen indicated the mTOR inhibitor rapamycin profile matched the signature of GC-sensitivity. We thus tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells, and found that it sensitized cells to glucocorticoid induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis, and that the combination of rapamycin and glucocorticoids has potential utility in ALL. Furthermore this approach represents a novel strategy for identification of promising combination therapies for cancer. Experiment Overall Design: primary acute lymphoblastic leukemia samples were determined to be sensitive or resistant to in vitro treatment with glucocorticoids. Samples were then hybrized to affymetrix microarrays
2009-04-04 | E-GEOD-5820 | biostudies-arrayexpress
Project description:Gene expression data of glucocorticoid resistant and sensitive acute lymphoblastic leukemia cell lines for the article: Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and constitute a central component in the therapy of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2), a kinase controlling glucose metabolism, was identified by us previously as GC response gene in expression profiling analyses performed in children with ALL during initial systemic GC mono-therapy. Since deregulation of glucose metabolism has been implicated in apoptosis induction, this gene and its relatives PFKFB1, 3, and 4 were further analyzed. Expression analyses in additional ALL children, non-leukemic individuals and leukemic cell lines confirmed frequent PFKFB2 induction by GC in most systems sensitive to GC-induced apoptosis, particularly in T-ALL cells. The 3 other family members, in contrast, were not or weakly expressed (PFKFB1 and 4) or not induced by GC (PFKFB3). Conditional PFKFB2 over-expression in the CCRF-CEM T-ALL in vitro model revealed that its 2 splice variants (15A and 15B) did not have any detectable effect on survival or cell cycle progression. Moreover, neither PFKFB2 splice variant significantly affected sensitivity to, or kinetics of, GC-induced apoptosis. Our data suggest that, at least in the model system investigated, PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of GC. Generation of the GC sensitive and resistant clones is described in Parson et al. FASEB J 2005 (Pubmed id 15637111). In brief GC sensitive clones were generated by limiting dilution subcloning from the GC sensitive T-ALL cell line CCRF-CEM-C7H2. To generate GC resistant clones the CCRF-CEM-C7H2 cell line was clutured in the presence of 10E-7 M dexametasone. Gene expression profiles of glucocorticoid (GC) resistant and sensitive T-ALL cells during GC treatment and corresponding control samples (cells treated with carrier control). GC induced regulation of PFKFB2 was determined in the various cell lines based on the expression intensities of the corresponding probe sets in GC treated and control samples.
2011-02-01 | E-GEOD-22152 | biostudies-arrayexpress
Project description:Drug resistance remains a major obstacle to successful cancer treatment. Here we use a novel approach to identify rapamycin as a glucocorticoid resistance reversal agent. A database of drug-associated gene expression profiles was screened for molecules whose profile overlapped with a gene expression signature of glucocorticoid (GC) sensitivity/resistance in Acute Lymphoblastic Leukemia (ALL) cells. The screen indicated the mTOR inhibitor rapamycin profile matched the signature of GC-sensitivity. We thus tested the hypothesis that rapamycin would induce GC sensitivity in lymphoid malignancy cells, and found that it sensitized cells to glucocorticoid induced apoptosis via modulation of antiapoptotic MCL1. These data indicate that MCL1 is an important regulator of GC-induced apoptosis, and that the combination of rapamycin and glucocorticoids has potential utility in ALL. Furthermore this approach represents a novel strategy for identification of promising combination therapies for cancer. Experiment Overall Design: CEM-C1 cells were treated with 10 nM rapamycin or DMSO and harvested for microarray analysis at 24 hours
2008-06-14 | E-GEOD-5821 | biostudies-arrayexpress