Expression Profiles of Responders versus Non-Responders with AML or MDS to the Novel Mitochondrial Inhibitor CPI-613
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jeff Chou
PROVIDER: E-GEOD-60350 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:To determine if there are differences in the gene expression profile of peripheral blood mononuclear cells in patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) who responded to CPI-613 when compared to those patients who did not respond we generated gene expression profiles from four responding patients and compared them to four non-responders. None of the gene expression profiles have been previously published. Here we describe the origins and provide associated clinical annotations with the hope that other investigators will be able to utilize this data in their own research.
2014-08-13 | GSE60350 | GEO
Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal. All 96 bone marrow samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation.
2011-01-01 | E-GEOD-21261 | biostudies-arrayexpress
Project description:The nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.
2021-09-22 | PXD021738 | Pride
Project description:Firstly, we extracted bone marrow cells from AML mouse models in four different timepoints (T0, T1, T2 and T3). And we used droplet-based single cell RNA sequencing technology to reveal the early-MDS, late-MDS, MDS-AML and AML four-stage landscape in a mouse AML model initiated by Myc overexpression. Also, we extracted one AML patient bone marrow sample to sequence by constructing library following 10X genomics platform. And integrated this data with four AML patients data from 10X genomics database to explain the molecular mechanism of splicing events of TMEM134 in AML. To verify the alternative splicing results, we used smartseq2 to construct the single cell library in T3. And combined TCGA-LAML and TARGET-AML database and our mouse function data, we identify the alternative splicing events of TMEM134 could drive the proliferation function in acute myelogenous leukemogenesis.
2023-01-30 | GSE142645 | GEO
Project description:Full Title: Multilineage Dysplasia (MLD) in AML correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: A comparison of 408 cases classified as “AML not otherwise specified” or “AML with myelodysplasia-related changes” The WHO classification of acute myeloid leukemia (AML) is hierarchically structured and integrates genetic information, data on patients’ history, and multilineage dysplasia (MLD). The category “AML with MDS-related changes” (AML-MRC) is separated from AML not otherwise specified (AML-NOS) by the presence of either MLD, MDS-related cytogenetics or MDS history. To clarify whether MLD alone is clinically relevant, we analyzed 408 adult patients categorized as AML-MRC or AML-NOS. EFS (Median 13.8 months vs. 16.0 months) and 3-year-OS (45.8% vs. 53.9%) did not differ significantly between patients with MLD and without. However, MLD correlated with pre-existing MDS (p<0.001) and MDS-related cytogenetics (p=0.035). Patients with MLD as sole AML-MRC criterion (AML-MLD-sole; n=90) had less frequently FLT3-ITD (p=0.032), and a lower median age than AML-NOS (n=232), but EFS, OS, and WBC did not differ significantly. Contrarily, patients with AML-NOS plus AML-MLD-sole (n=323) versus patients with MDS history or MDS-related cytogenetics (n=85) had better EFS (16.9 vs. 10.7 months; p=0.005) and 3-year-OS (55.8% vs. 32.5%; p=0.001). Gene expression profiles were measured for a subset of 96 patients. Analysis of the expression data showed distinct clusters for AML-MLD-sole and AML-NOS versus AML with MDS-related cytogenetics or MDS history. Thus, MLD demonstrated no independent clinical impact, while cytogenetics and MDS history were of prognostic relevance. This data suggest modifications in a revised WHO proposal.
2011-01-01 | GSE21261 | GEO
Project description:Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a lethal complication of cancer treatment. Although t-MDS/AML development is associated with known genotoxic exposures, its pathogenesis is not well understood and methods to predict risk of development of t-MDS/AML in individual cancer survivors are not available. We performed microarray analysis of gene expression in samples from patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and controls that did not develop t-MDS/AML after aHCT. CD34+ progenitor cells from peripheral blood stem cell (PBSC) samples obtained pre-aHCT from t-MDS/AML cases and matched controls, and bone marrow (BM) samples obtained at time of development of t-MDS/AML, were studied. Significant differences in gene expression were seen in PBSC obtained pre-aHCT from patients who subsequently developed t-MDS/AML compared to controls. Genetic alterations in pre-aHCT samples were related to mitochondrial function, protein synthesis, metabolic regulation and hematopoietic regulation. Progression to overt t-MDS/AML was associated with additional alterations in DNA repair and DNA-damage checkpoint genes. Altered gene expression in PBSC samples were validated in an independent group of patients. An optimal 63-gene PBSC classifier derived from the training set accurately distinguished patients who did or did not develop t-MDS/AML in the independent test set. These results indicate that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and can accurately identify those at risk of developing this complication. PBSC samples obtained pre-aHCT and BM samples at the time of development of t-MDS/AML post-HCT were studied. The training set consisted of 18 patients who developed t-MDS/AML (M-bM-^@M-^]casesM-bM-^@M-^]) after aHCT, matched with 37 controls who underwent aHCT, but did not develop t-MDS/AML. One to three controls were selected per case, matched for primary diagnosis (HL/NHL), age at aHCT (M-BM-110years), and ethnicity (Caucasians, African-Americans, Hispanics, other). The length of follow-up after aHCT for controls was longer than the time to t-MDS/AML in the corresponding case. The results of the training set were validated in an independent group of 36 patients (test set) consisting of 16 cases that developed t-MDS/AML post-aHCT and 20 matched controls. In the test set, 55 PBSC samples from 18 cases and 37 matched controls were studied. BM samples from time of development of t-MDS/AML were available for 12 cases, and from 21 matched controls obtained at a comparable time from aHCT. For validation, 36 PBSC samples from 16 cases and 20 matched controls were studied. All samples had been cryopreserved as mononuclear cells. After thawing, samples were labeled with anti-CD34-APC and anti-CD45-FITC and CD34+CD45dim cells were selected using flow cytometry. Total RNA was extracted using the RNeasy kit. RNA from 1000 cells was amplified and labeled using GeneChipM-BM-. Two-Cycle Target Labeling and Control Reagents from Affymetrix. 15 M-BM-5g of cRNA each was hybridized to Affymetrix HG U133 plus 2.0 Arrays. Microarray data were analyzed using R (version 2.9) with genomic analysis packages from Bioconductor (version 2.4). Data for PBSC and BM samples were normalized separately using robust multiarray averages with consideration of GC content (GCRMA). Probesets with low expression or variability were filtered. Expression of genes represented by multiple probesets was set as the median of the probesets. Using conditional logistic model (CLM) to retain matching between cases and controls, we analyzed the magnitude of association [expressed as odds ratio (OR)] between t-MDS/AML and i) gene expression levels in PBSC at the pre-aHCT time point; ii) gene expression levels in BM at time of t-MDS/AML; and iii) change of expression of individual genes from PBSC to time of t-MDS/AML. False discovery rate (FDR) was applied to adjust for multiple testing. Gene set enrichment analysis (GSEA) was performed on ranked lists of genes differentially expressed between cases and controls. Where multiple significant gene sets were related to each other, analysis was performed to identify a subset of common enriched genes. Average gene expression was calculated for each set and heatmaps plotted to show the contrasts between cases and controls. Gene Ontology (GO) and pathway analysis was performed using DAVID 2008 and Ingenuity IPA 7.5 respectively, retaining genes with z-scores M-bM-^IM-%1.8 or M-bM-^IM-$-1.8, and M-bM-^IM-%1.5-fold change in OR between cases and controls. The association between gene expression in the PBSC product and subsequent development of t-MDS/AML identified in the training set was validated in an independent test set of 36 PBSC sample procured from patients who developed t-MDS/AML after aHCT (16 cases) or did not (20 controls). Pre-processing, normalization and filtering procedures for the test set were identical to the training set. Differential expression between cases and controls was analyzed using CLM. GSEA analysis was performed on the ranked list of differentially expressed genes. Prediction analysis of microarray (PAM) was used to derive a prognostic gene signature from the training set to classify patients as case or control. PAM uses the M-bM-^@M-^\nearest shrunken centroidM-bM-^@M-^] approach and 10-fold cross-validation to select a parsimonious gene expression signature that can classify samples with minimal misclassification. PAM was applied to genes common to both datasets. Based on the misclassification error in cross-validation, a 63-gene signature was selected for prediction using the test data.
2011-12-12 | E-GEOD-23025 | biostudies-arrayexpress
Project description:Ringsideroblasts(RS) emerge as result of aberrant erythroid differentiation leading to excessive mitochondrial iron accumulation. This feature is characteristic for myelodysplastic syndromes with mutations in spliceosome gene SF3B1. However, RS can also be observed in patients diagnosed with acute myeloid leukemia (AML). The objective of this study was to characterize the presence of RS in a cohort of 109 AML and 17 high-risk MDS patients. Clinically, RS-AML is enriched for ELN adverse-risk (55%). In line with this finding, 35% of all cases had complex cytogenetic aberrancies and TP53 was most recurrently mutated in this cohort (42%), followed by DNMT3A (29%), RUNX1 (21%) and ASXL1 (19%). In contrast to RS-MDS, the incidence of SF3B1 mutations was low (8%). Whole exome sequencing and SNP array analysis on a subset of patients did not uncover one single defect underlying the RS phenotype. Shared genetic defects between erythroblasts and total mononuclear cell fraction indicate common ancestry for the erythroid lineage and the myeloid blast cells in RS-AML patients. Gene expression analysis by performing RNA sequencing on CD34+ AML cells revealed differential gene expression between RS-AML and a separate AML cohort, including genes involved in megakaryocytic/erythroid differentiation and mRNA splicing. Furthermore, several heme-metabolism-related genes were found upregulated in RS-AML, as was observed in SF3B1mut MDS. These results demonstrate that erythroblasts share ancestry with malignant myeloid blast cells in RS-AML. The genetic background of RS-AML differs from that of RS-MDS, however downstream effector pathways may be comparable, providing a possible explanation for presence of RS in AML.
2020-03-17 | GSE127861 | GEO
Project description:This study includes 2 cohorts of samples. First cohort consists out of BM aspirates from 4 healthy individuals and 12 patients diagnosed with AML, MDS or CMML. Second cohort includes 5 healthy individuals and 17 patients diagnosed with AML, MDS or CMML. MDS and CMML patients were treated with 5-AZA on 6 cycles and samples were obtained before the treatment and 15 days after 1 and 6 rounds of treatment.
2019-12-10 | E-MTAB-8208 | biostudies-arrayexpress
Project description:Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a lethal complication of cancer treatment. Although t-MDS/AML development is associated with known genotoxic exposures, its pathogenesis is not well understood and methods to predict risk of development of t-MDS/AML in individual cancer survivors are not available. We performed microarray analysis of gene expression in samples from patients who developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and controls that did not develop t-MDS/AML after aHCT. CD34+ progenitor cells from peripheral blood stem cell (PBSC) samples obtained pre-aHCT from t-MDS/AML cases and matched controls, and bone marrow (BM) samples obtained at time of development of t-MDS/AML, were studied. Significant differences in gene expression were seen in PBSC obtained pre-aHCT from patients who subsequently developed t-MDS/AML compared to controls. Genetic alterations in pre-aHCT samples were related to mitochondrial function, protein synthesis, metabolic regulation and hematopoietic regulation. Progression to overt t-MDS/AML was associated with additional alterations in DNA repair and DNA-damage checkpoint genes. Altered gene expression in PBSC samples were validated in an independent group of patients. An optimal 63-gene PBSC classifier derived from the training set accurately distinguished patients who did or did not develop t-MDS/AML in the independent test set. These results indicate that genetic programs associated with t-MDS/AML are perturbed long before disease onset, and can accurately identify those at risk of developing this complication.
2011-12-12 | GSE23025 | GEO
Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-M-NM-:M-NM-^R activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-M-NM-:B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-M-NM-:B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-M-NM-:B to sustain TRAF6/NF-M-NM-:B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML. Four del(5q) MDS/AML patients with low miR-146a expression (5284, 8839, 8285, 4233) and 5 with high miR-146a expression (7957, 5534, 4688, 4982, 8412) were selected for microarray assay. RNA was reverse transcribed and labeled, and hybridized onto the GeneChip Human Gene 1.0 ST Array. A total of nine samples were included, and two groups are assigned based on miR-146a expression. Comparison comprises mRNA expression profile of low miR-146a group v.s. high miR-146a group.
2014-08-23 | E-GEOD-60649 | biostudies-arrayexpress