ZBTB16, a glucocorticoid response gene in acute lymphoblastic leukemia, interferes with glucocorticoid-induced apoptosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE15820 | GEO | 2010/05/07
SECONDARY ACCESSION(S): PRJNA116739
REPOSITORIES: GEO
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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: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.
2011-02-01 | GSE22152 | GEO
Project description:Article title: 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 a 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. Gene expression profiles of 4 non-leukemic individuals (1 healthy and 3 with epilepsy) were generated from mononuclear cells isolated from peripheral blood samples before, and after 2, 6, and 24 hours of in-vivo glucocorticoid treatment.
2011-02-01 | E-GEOD-22779 | biostudies-arrayexpress
Project description:Article title: 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 a 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.
2011-02-01 | GSE22779 | GEO
Project description:Glucocorticoids (GC) have a major impact on the biology of normal and malignant cells of the lymphoid lineage. This includes induction of apoptosis which is exploited in the therapy of acute lymphoblastic leukemia (ALL) and related lymphoid malignancies. MicroRNAs (miRNAs) and the related mirtrons are ~22 nucleotide RNA molecules implicated in the control of essential biological functions including proliferation, differentiation and apoptosis. They derive from polymerase-II transcripts but whether GCs regulate miRNA-encoding transcription units is not known. We investigated miRNA/mirtron expression and GC regulation in 8 ALL in vitro models and 13 ALL children undergoing systemic GC monotherapy using a combination of expression profiling techniques, real time RT-PCR and northern blotting to detect mature miRNAs and/or their precursors. We identified a number of GC-regulated miRNAs/mirtrons, including the myeloid-specific miR-223 and the apoptosis and cell cycle arrest-inducing mir15~16 cluster. Thus, the observed complex changes in miRNA/mirtron expression during GC treatment might contribute to the anti-leukemic GC effects in a cell context dependent manner. Experiment Overall Design: Glucocorticoid-sensitive T-ALL cell line CCRF-CEM-C7H2 was treated in 3 independent experiments either with 100nM dexametasone (a glucocorticoid) or 0.1% ethanol as an empty carrier control. Samples were taken at various timepoints (6 and 24 hours), RNA extracted and hybridized onto Affymetrix HGU133-plus2 microarrays. The microarray dataset was subsetted to probesets targetting potential primary microRNA transcripts (pri-miRNAs). Differentially expressed pri-miRNAs were identified for the comparisons of the 6h GC versus 6h EtOH (control) and for the 24h GC versus 24h EtOH (control) samples.
2009-01-25 | E-GEOD-11336 | 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. This SuperSeries is composed of the following subset Series:; GSE5820: Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL-1 and glucocorticoid resistance; GSE5821: Rapamycin treatment of CEM_C1 cells 24 hours; GSE5822: Rapamycin treated CEM-C1 cells 3 hours Experiment Overall Design: Refer to individual Series
2008-11-06 | E-GEOD-5824 | biostudies-arrayexpress
Project description:Glucorticoids (GCs) are steroid hormones with a wide range of physiological actions in different cell types and tissues. Their ability to induce apoptosis in malignant cells of the lymphoid lineage is exploited since decades in the treatment of childhood acute lymphoblastic leukemia (ALL), the molecular mechanism of this cell death induction being however still unknown. Using an integrative approach we delineated the transcriptional response of a preB- and a T-ALL model system employing Exon microarrays and identified in vivo interactions of the transcription factor GC receptor (GR) with genes' promoters in the same samples using the ChIP-on-chip technology. We did find differences in GR-DNA interaction in the genes' promoters between the two cell systems and also in extent and kinetics of GC mediated gene regulation. The overall response was stronger in CEM-C7H2 T-ALL cells where it was also accompanied by a stronger autoup-regulation of the GR gene. Considering the differing kinetics we furthermore defined a set of common response genes. These response genes were enriched in apoptosis related gene ontology processes, and about half of them yielded also GR enrichment in the respective promoter regions. Globally, the presence of GR at gene's promoters was higher for GC induced compared to repressed genes, indicating that GR mediates gene repression by interaction with distant enhancer regions or by cross-talk with other transcription factors. In order to identify the genes' GC regulated transcript variants we analyzed the data set also at the level of individual exons and predicted first exons of GC induced isoforms. We could thus define GC regulated variants of response genes, did however also identify first exons not corresponding to any known transcript. We reconfirmed these results for the genes ATP4B, GPR98, TBCD and ZBTB16 and identified for the latter also a novel exon employing 5' nested amplification of cDNA ends. Expression and regulation of this and all downstream exons of ZBTB16 was further verified by real time RT-PCR in 4 different preB-ALL cell lines. Thus, besides potential other novel gene isoforms, GCs induce a novel short transcript variant of ZBTB16 in preB-ALL cells. Finally, the implemented bioinformatic methods may be useful also for other high density microarray data sets to identify alternative splice events and transcript variant expression.
2011-11-15 | GSE29049 | GEO
Project description:Glucorticoids (GCs) are steroid hormones with a wide range of physiological actions in different cell types and tissues. Their ability to induce apoptosis in malignant cells of the lymphoid lineage is exploited since decades in the treatment of childhood acute lymphoblastic leukemia (ALL), the molecular mechanism of this cell death induction being however still unknown. Using an integrative approach we delineated the transcriptional response of a preB- and a T-ALL model system employing Exon microarrays and identified in vivo interactions of the transcription factor GC receptor (GR) with genes' promoters in the same samples using the ChIP-on-chip technology. We did find differences in GR-DNA interaction in the genes' promoters between the two cell systems and also in extent and kinetics of GC mediated gene regulation. The overall response was stronger in CEM-C7H2 T-ALL cells where it was also accompanied by a stronger autoup-regulation of the GR gene. Considering the differing kinetics we furthermore defined a set of common response genes. These response genes were enriched in apoptosis related gene ontology processes, and about half of them yielded also GR enrichment in the respective promoter regions. Globally, the presence of GR at gene's promoters was higher for GC induced compared to repressed genes, indicating that GR mediates gene repression by interaction with distant enhancer regions or by cross-talk with other transcription factors. In order to identify the genes' GC regulated transcript variants we analyzed the data set also at the level of individual exons and predicted first exons of GC induced isoforms. We could thus define GC regulated variants of response genes, did however also identify first exons not corresponding to any known transcript. We reconfirmed these results for the genes ATP4B, GPR98, TBCD and ZBTB16 and identified for the latter also a novel exon employing 5' nested amplification of cDNA ends. Expression and regulation of this and all downstream exons of ZBTB16 was further verified by real time RT-PCR in 4 different preB-ALL cell lines. Thus, besides potential other novel gene isoforms, GCs induce a novel short transcript variant of ZBTB16 in preB-ALL cells. Finally, the implemented bioinformatic methods may be useful also for other high density microarray data sets to identify alternative splice events and transcript variant expression.
2011-11-15 | GSE29057 | GEO
Project description:Glucorticoids (GCs) are steroid hormones with a wide range of physiological actions in different cell types and tissues. Their ability to induce apoptosis in malignant cells of the lymphoid lineage is exploited since decades in the treatment of childhood acute lymphoblastic leukemia (ALL), the molecular mechanism of this cell death induction being however still unknown. Using an integrative approach we delineated the transcriptional response of a preB- and a T-ALL model system employing Exon microarrays and identified in vivo interactions of the transcription factor GC receptor (GR) with genes' promoters in the same samples using the ChIP-on-chip technology. We did find differences in GR-DNA interaction in the genes' promoters between the two cell systems and also in extent and kinetics of GC mediated gene regulation. The overall response was stronger in CEM-C7H2 T-ALL cells where it was also accompanied by a stronger autoup-regulation of the GR gene. Considering the differing kinetics we furthermore defined a set of common response genes. These response genes were enriched in apoptosis related gene ontology processes, and about half of them yielded also GR enrichment in the respective promoter regions. Globally, the presence of GR at gene's promoters was higher for GC induced compared to repressed genes, indicating that GR mediates gene repression by interaction with distant enhancer regions or by cross-talk with other transcription factors. In order to identify the genes' GC regulated transcript variants we analyzed the data set also at the level of individual exons and predicted first exons of GC induced isoforms. We could thus define GC regulated variants of response genes, did however also identify first exons not corresponding to any known transcript. We reconfirmed these results for the genes ATP4B, GPR98, TBCD and ZBTB16 and identified for the latter also a novel exon employing 5' nested amplification of cDNA ends. Expression and regulation of this and all downstream exons of ZBTB16 was further verified by real time RT-PCR in 4 different preB-ALL cell lines. Thus, besides potential other novel gene isoforms, GCs induce a novel short transcript variant of ZBTB16 in preB-ALL cells. Finally, the implemented bioinformatic methods may be useful also for other high density microarray data sets to identify alternative splice events and transcript variant expression.
2011-11-15 | GSE29003 | GEO
Project description:Glucorticoids (GCs) are steroid hormones with a wide range of physiological actions in different cell types and tissues. Their ability to induce apoptosis in malignant cells of the lymphoid lineage is exploited since decades in the treatment of childhood acute lymphoblastic leukemia (ALL), the molecular mechanism of this cell death induction being however still unknown. Using an integrative approach we delineated the transcriptional response of a preB- and a T-ALL model system employing Exon microarrays and identified in vivo interactions of the transcription factor GC receptor (GR) with genes' promoters in the same samples using the ChIP-on-chip technology. We did find differences in GR-DNA interaction in the genes' promoters between the two cell systems and also in extent and kinetics of GC mediated gene regulation. The overall response was stronger in CEM-C7H2 T-ALL cells where it was also accompanied by a stronger autoup-regulation of the GR gene. Considering the differing kinetics we furthermore defined a set of common response genes. These response genes were enriched in apoptosis related gene ontology processes, and about half of them yielded also GR enrichment in the respective promoter regions. Globally, the presence of GR at gene's promoters was higher for GC induced compared to repressed genes, indicating that GR mediates gene repression by interaction with distant enhancer regions or by cross-talk with other transcription factors. In order to identify the genes' GC regulated transcript variants we analyzed the data set also at the level of individual exons and predicted first exons of GC induced isoforms. We could thus define GC regulated variants of response genes, did however also identify first exons not corresponding to any known transcript. We reconfirmed these results for the genes ATP4B, GPR98, TBCD and ZBTB16 and identified for the latter also a novel exon employing 5' nested amplification of cDNA ends. Expression and regulation of this and all downstream exons of ZBTB16 was further verified by real time RT-PCR in 4 different preB-ALL cell lines. Thus, besides potential other novel gene isoforms, GCs induce a novel short transcript variant of ZBTB16 in preB-ALL cells. Finally, the implemented bioinformatic methods may be useful also for other high density microarray data sets to identify alternative splice events and transcript variant expression.
2011-11-15 | GSE29056 | GEO