Unknown,Transcriptomics,Genomics,Proteomics

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Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and JNK inhibitors as a re-sensitising therapy

ABSTRACT: Glucocorticoids (GC) are pivotal in the treatment of childhood acute lymphoblastic leukaemia (ALL) but resistance is a continuing clinical problem with the underlying mechanisms still unclear. An isobaric tag proteomic approach was used to compare protein profiles of the B lineage ALL GC-sensitive cell line, PreB 697, and its GC-resistant sub-line, R3F9, before and after dexamethasone exposure. Two transcription factors involved in B- cell differentiation, PAX5 and IRF4, were differentially regulated in the PreB 697 compared to the R3F9 cell line in response to GC. PAX5 basal protein expression was less in R3F9 compared to its GC-sensitive parent and was confirmed to be lower in other GC-resistant sub-lines of Pre B697 and was associated with a decreased expression of the PAX5 transcriptional target, CD19. Gene set enrichment analysis of microarray data from the cell lines showed that increasing GC-resistance was associated with differentiation from preB-II to an immature B-lymphocytes stage. GC resistant sub lines were shown to have a higher levels of p-JNK compared to the parent line and JNK inhibition caused re-sensitisation to GC. Reduced CD19 levels accompanying GC resistance was also apparent in some clinical samples, with high levels of MRD persisting after GC containing induction chemotherapy. Thus, quantitative proteomic analysis reveals a role for PAX5 and maturation as a recurrent mechanism underlying glucocorticoid resistance in ALL and identifies JNK inhibitors as a possible re-sensitising therapy. Gene expresion profiling of GC-sensitive and resistant precursor B-ALL cells. Gene set enrichment analysis (GSEA) was used to analyse the state of differentiation of GC-resistant sub-lines and genes were ranked according to the correlation of gene expression with dexamethasone IC50 values for the individual sub-lines.

ORGANISM(S): Homo sapiens

SUBMITTER: Johannes Rainer

PROVIDER: E-GEOD-63335 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and re-sensitization by JNK inhibition.

Nicholson Lindsay L Evans Caroline A CA Matheson Elizabeth E Minto Lynne L Keilty Christopher C Sanichar Maryna M Case Marian M Schwab Claire C Williamson Daniel D Rainer Johannes J Harrison Christine J CJ Kofler Reinhard R Hall Andrew G AG Redfern Christopher P F CP Whetton Anthony D AD Irving Julie A E JA

British journal of haematology 20150827 4

Glucocorticoid (GC) resistance is a continuing clinical problem in childhood acute lymphoblastic leukaemia (ALL) but the underlying mechanisms remain unclear. A proteomic approach was used to compare profiles of the B-lineage ALL GC-sensitive cell line, PreB 697, and its GC-resistant sub-line, R3F9, pre- and post-dexamethasone exposure. PAX5, a transcription factor critical to B-cell development was differentially regulated in the PreB 697 compared to the R3F9 cell line in response to GC. PAX5 b ...[more]

PMID: 26310606

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Project description:The beneficial effects of glucocorticoids (GCs) in acute lymphoblastic leukemia (ALL) are based on their ability to induce apoptosis. Omics technologies such as DNA microarray analysis are widely used to study the changes in gene expression and have been successfully implemented in biomarker identification. In addition, time series studies of gene expression enable the identification of correlations between kinetic profiles of glucocorticoid receptor (GR) target genes and diverse modes of transcriptional regulation. This study presents a genome-wide microarray analysis of both our and published Affymetrix HG-U133 Plus 2.0 data in GCs-sensitive and -resistant ALL. GCs-sensitive CCRF-CEM-C7-14 cells were treated with dexamethasone at three time points (0 h, 2 h and 10 h). The treated samples were then compared to the control (0 h). The published data used were as follows: GSE2677: GSM51674: B-ALL-24-24h GSM51675: B-ALL-24-6h GSM51676: B-ALL-24-0h GSM51680: B-ALL-17-24h GSM51681: B-ALL-17-8h GSM51682: B-ALL-17-0h GSM51677: B-ALL-13-24h GSM51678: B-ALL-13-8h GSM51679: B-ALL-13-0h GSM51683: B-ALL-31-24h GSM51684: B-ALL-31-6h GSM51685: B-ALL-31-0h GSM51686: B-ALL-32-24h GSM51687: B-ALL-32-6h GSM51688: B-ALL-32-0h GSM51689: B-ALL-33-24h GSM51690: B-ALL-33-6h GSM51691: B-ALL-33-0h GSM51692: B-ALL-37-24h GSM51693: B-ALL-37-6h GSM51694: B-ALL-37-0h GSM51695: B-ALL-38-24h GSM51696: B-ALL-38-6h GSM51697: B-ALL-38-0h GSM51698: B-ALL-40-24h GSM51699: B-ALL-40-6h GSM51700: B-ALL-40-0h GSM51701: B-ALL-43-24h GSM51702: B-ALL-43-6h GSM51703: B-ALL-43-0h GSM51707: T-ALL-25-24h GSM51708: T-ALL-25-6h GSM51709: T-ALL-25-0h GSM51704: T-ALL-20-24h GSM51705: T-ALL-20-8h GSM51706: T-ALL-20-0h GSM51710: T-ALL-2-24h GSM51711: T-ALL-2-8h GSM51712: T-ALL-2-0h GSE2842 GSM60545: S-Line-PreB-6h-EtOH GSM60546: S-Line-PreB-6h-GC GSM60547: S-Line-PreB-24h-GC GSM60542: S-Line-C7H2-6h-EtOH GSM60543: S-Line-C7H2-6h-GC GSM60544: S-Line-C7H2-24h-GC GSM60560: R-Line-CEMC1-6h-EtOH GSM60561: R-Line-CEMC1-6h-GC GSM60562: R-Line-CEMC1-24h-GC GSM60564: R-Line-C7R1-6h-EtOH GSM60566: R-Line-C7R1-6h-GC GSM60576: R-Line-C7R1dim-low-6h-EtOH GSM60578: R-Line-C7R1dim-low-6h-GC GSM60579: R-Line-C7R1dim-low-24h-GC GSM60581: R-Line-PreB-6h-EtOH GSM60583: R-Line-PreB-6h-GC GSM60584: R-Line-PreB-24h-EtOH GSM60586: R-Line-PreB-24h-GC GSM60548: C-Line-CEMC1-ratGR-6h-EtOH GSM60549: C-Line-CEMC1-ratGR-6h-GC GSM60550: C-Line-CEMC1-ratGR-24h-GC GSM60551: C-Line-C7R1dim-high-6h-EtOH GSM60552: C-Line-C7R1dim-high-6h-GC GSM60553: C-Line-C7R1dim-high-24h-GC

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.

Dataset Information

Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and JNK inhibitors as a re-sensitising therapy

Publications

Quantitative proteomic analysis reveals maturation as a mechanism underlying glucocorticoid resistance in B lineage ALL and re-sensitization by JNK inhibition.

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