Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA91647 | ENA |
REPOSITORIES: ENA
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Project description:Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients, and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting cross-resistance to prednisolone, vincristine, asparaginase and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37%±13% 5-year DFS). Keywords = Acute lymphoblastic leukemia Keywords = cross-resistance Keywords: other
2005-04-01 | GSE2351 | GEO
Project description:Treatment resistance as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells, which is reflected in the gene expression pattern, and that resistance to chemotherapy can be predicted prior to treatment. To test these hypotheses, gene expression signatures of ALL samples with a high MRD load (MRD-HR) were compared to those of samples without measurable MRD (MRD-SR) during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes low expressed in resistant samples were predominantly associated with cell cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. As treatment response could be predicted with a high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.
2005-11-09 | E-SMDB-2922 | biostudies-arrayexpress
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 | GSE215187 | 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. 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:The development of a clinically relevant xenograft model of pediatric acute lymphoblastic leukemia, using a 4-drug treatment regimen designed to mimic pediatric remission induction therapy. Relapse and acquired drug resistance in T-cell acute lymphoblastic leukemia (T-ALL) remains a significant clinical problem. This study was designed to establish a preclinical model of resistance to induction therapy in childhood T-ALL to examine the emergence of drug resistance and identify novel therapies. We performed transcription profiling by array of human CD45-positive human lymphocytes from patients with acute pediatric lymphoblastic leukemia, and from xenografted NOD/SCID mice treated with vincristine, daunorubicin, dexamethasone and L-asparagine. Several different treatment regimes were used in this study (VLXD, VLXDR, VLXD2, VXL and VLXD2-ALL31) and are summarised in the protocols associated with this submission.
2013-11-01 | E-MEXP-3916 | biostudies-arrayexpress
Project description:Treatment resistance as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells, which is reflected in the gene expression pattern, and that resistance to chemotherapy can be predicted prior to treatment. To test these hypotheses, gene expression signatures of ALL samples with a high MRD load (MRD-HR) were compared to those of samples without measurable MRD (MRD-SR) during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes low expressed in resistant samples were predominantly associated with cell cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. As treatment response could be predicted with a high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Keywords: disease_state_design Using regression correlation
2006-01-18 | E-GEOD-4057 | biostudies-arrayexpress
Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.
2020-01-29 | MSV000084862 | MassIVE
Project description:Transcriptome of childhood acute lymphoblastic leukemia
| PRJNA809691 | ENA
Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP
Project description:Proteogenomic analysis and genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of High hyperdiploid childhood acute lymphoblastic leukemia.
2019-02-25 | PXD010175 | Pride