Comparative intraindividual transcriptome analysis of B-precursor ALL of childhood
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42221 | GEO | 2013/09/17
SECONDARY ACCESSION(S): PRJNA179347
REPOSITORIES: GEO
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Project description:The objective of this study was the assessment of transcriptional dysregulation in particular with regard to B-cell differentiation factors. Most studies focus on cross-section analyses of various leukemia subtypes to identify differentially regulated genes lacking suitable reference models. Here we applied comparative intraindividual transcriptome analysis of B-precursor ALL of childhood, which introduces a side-by-side analysis of leukemic cells and matched normal lymphoblasts from the same individual in complete continuous remission after the end of re-induction therapy. This approach reduces noise by eliminating interindividual variability. Comparative matched pair analysis of (single sorted) initial leukemia and single sorted lymphoblasts isolated from the same individual, n=4 pairs, reference samples are the single sorted normal lymphoblasts. Please note that there are sorted samples form only three of the patients. Due to experimental circumstances, a "sorted" sample from the last patient was not included.
2013-09-17 | E-GEOD-42221 | biostudies-arrayexpress
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Project description:Glucocorticoids (GCs) cause cell cycle arrest and cell death in malignant lymphoblasts and constitute a principal component in the treatment of childhood acute lymphoblastic leukemia (chALL). To address the molecular mechanism of the anti-leukemic GC effects, we performed microarray-based whole-genome expression profiling of lymphoblasts from 46 patients undergoing systemic GC mono-therapy and combined these data with clinical information (e.g., molecular genotype, reduction in peripheral blood lymphoblasts, GC bioactivity in the patient's blood) using differential gene expression with GO analyses, regression modeling correlating transcriptional with clinical response, and an iterative elastic net approach to address combinatorial effects of gene expression and regulation. Our analysis revealed that, although there are a number of common response genes, the transcriptional response to GC in vivo varies considerably in the different molecular subtypes of this disease. Regarding the anti-leukemic response, repression of mRNA for key regulators of G2/M transition was commonly observed in all subtypes whereas we failed to observe a common transcriptional control of apoptosis genes. Although sets of genes were identified which in combination appear to contribute to the apoptotic response, the data as a whole suggest that GC-induced cell death does not result from conserved transcriptional regulation of the apoptotic machinery itself but might rather result from a wide spread deregulation of gene expression.
2017-09-22 | GSE73578 | GEO
Project description:The purpose of this study was the principal investigation and frequency of RTK expression in primary T-ALLs. Primary initial T-ALLs were assessed regarding their transcriptome-wide expression profiles and screend for prominent RTK expression. Naive primary T-ALL samples were evaluated with regard to global mRNA expression and screened for prominent RTK expression. The dataset was used to investigate RTK expression frequencies in T-ALLs.
2014-11-03 | E-GEOD-42038 | biostudies-arrayexpress
Project description:Glucocorticoids (GC) are in most chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukaemia (ALL) for their ability to induce apoptosis in malignant blast. The underlying mechanism, however, has so far only been investigated in model systems. This study comprises Affymetrix hgu133 plus 2.0 analyses of Peripheral blood lymphoblasts purified at three time points (0h, 6-8h, 24h after treatment initiation) from 13 children under therapy for ALL . Treated samples were compared to untreated (0h). This series consists of this set of microarrays. For comparison, expression profiles were generated from an adult ALL patient, peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and -resistant ALL cell lines and mouse thymocytes treated with GC in vivo and in vitro. Findings. An essentially complete list of GC-regulated candidate genes in clinical settings experimental and was generated, enabling immediate analysis of any gene with respect to its potential significance for GC-induced apoptosis in these systems. Gene regulations previously thought responsible for cell death in experimental systems were reconfirmed in few children only. In contrast, a small number of genes, most not implicated in GC-induced apoptosis previously, were co-ordinately regulated in the majority of children. Keywords = ALL Keywords = apoptosis Keywords = glucocorticoid Keywords = leukemia Keywords = pediatric oncology Keywords: other
2005-11-14 | GSE2677 | GEO
Project description:We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1x10-5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4x10-15, odds ratio[OR]=1.91; rs10994982, P=5.7x10-9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 x10-5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes. We used microarrays to detail the global program of gene expression in primary leukemic blasts cells from children diagnosed with acute lymphoblastic leukemia.
2009-08-16 | E-GEOD-17195 | biostudies-arrayexpress
Project description:We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1x10-5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4x10-15, odds ratio[OR]=1.91; rs10994982, P=5.7x10-9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 x10-5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes.
2009-08-16 | GSE17195 | GEO
Project description:Glucocorticoids (GC) are in most chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukaemia (ALL) for their ability to induce apoptosis in malignant blast. The underlying mechanism, however, has so far only been investigated in model systems. This study comprises Affymetrix hgu133 plus 2.0 analyses of Peripheral blood lymphoblasts purified at three time points (0h, 6-8h, 24h after treatment initiation) from 13 children under therapy for ALL . Treated samples were compared to untreated (0h). For comparison, expression profiles were generated from an adult ALL patient, peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and -resistant ALL cell lines and mouse thymocytes treated with GC in vivo and in vitro. This second series comprises the additional samples mentioned above. Findings. An essentially complete list of GC-regulated candidate genes in clinical settings experimental and was generated, enabling immediate analysis of any gene with respect to its potential significance for GC-induced apoptosis in these systems. Gene regulations previously thought responsible for cell death in experimental systems were reconfirmed in few children only. In contrast, a small number of genes, most not implicated in GC-induced apoptosis previously, were co-ordinately regulated in the majority of children. Keywords: treatment response
2005-11-14 | GSE2842 | GEO
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2023-02-23 | MSV000091352 | MassIVE
Project description:Gut bacterial β-glucuronidases (GUS) promote the toxic side effects of therapeutics by reactivating drugs from their inactive glucuronide conjugates. It is increasingly clear that the interindividual variability of bacterial GUS-producing species in the gut microbiota contributes to differential drug responses. Indeed, the anticancer drug irinotecan exhibits variable clinical toxicity outcomes that have been linked to interindividual differences in the composition of the gut microbiota. However, identification of the specific GUS enzymes responsible for drug metabolism in the context of the complexity of the human fecal microbiota has not been achieved. Here we pinpoint the specific bacterial GUS enzymes that reactivate SN-38, the active metabolite of irinotecan, from complex human fecal microbiota samples with activity-based protein profiling (ABPP). We identify and quantify gut bacterial GUS enzymes from human feces with ABPP-enabled proteomics and then integrate this information with ex vivo kinetics to reveal the specific GUS enzymes responsible for the reactivation of SN-38. The same ABPP approach also reveals the molecular basis for differential gut bacterial GUS inhibition between human fecal samples. Taken together, this work provides an unprecedented pipeline to identify the specific bacterial GUS enzymes responsible for drug-induced GI toxicity from the complexity of human feces, which may serve as highly precise biomarkers of clinical outcomes for irinotecan and other therapeutics.
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