Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated with Outcomes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE165656 | GEO | 2021/07/18
REPOSITORIES: GEO
Similar Datasets
Project description:Decoupling Lineage-Associated Genes in Acute Myeloid Leukemia Reveals Inflammatory and Metabolic Signatures Associated with Outcomes
| PRJNA695269 | ENA
Project description:Context: In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immune-deficient mice indicating that human acute myeloid leukemia (AML) is organized as a cellular hierarchy driven by self-renewing leukemia stem cells (LSC). This model has significant implications for the development of novel therapies, but its clinical significance remains unclear. Objective: To measure associations between a leukemic stem cell expression signature and clinical outcomes in AML. Design, Setting, and Patients: We defined a gene expression signature of LSC-enriched subpopulations from primary AML patient samples and xenografts, based on a functional definition in transplantation assays. Using previously published gene expression data of bulk AML from four independent cohorts totaling 1047 patients, we performed a retrospective cohort study, defining an LSC score and evaluating it for associations with known predictors of risk including cytogenetic subtype and molecular mutations, and as an independent prognostic factor. Main Outcome Measures: Reproducible associations between a leukemic stem cell signature and overall, event-free, and relapse-free survival. Results: The LSC score was similar across most AML subtypes, but was lower in promyelocytic leukemia, and prognostically favorable cases harboring NPM1 or CEBPA mutations. Strikingly, high scores associated with inferior overall (OS), event-free (EFS), and relapse-free survival (RFS) in these independent cohorts, whether considering patients with a normal karyotype [hazard ratio (HR) range for OS 1.13-1.18, p<0.012 in all cases], or those with cytogenetic anomalies (HR range for OS 1.07-1.15, p<0.01 in all cases). In multivariate analysis, the LSC score was associated with poor outcomes independently of age, FLT3 or NPM1 mutations, and cytogenetic risk group, and added to their prognostic value. Conclusions: High expression of a leukemic stem cell gene expression signature is independently associated with adverse outcomes in AML
2010-12-22 | GSE24006 | GEO
Project description:The study investigated the abberrent DNA methylation in correlation with gene expression in cytogenetic normal acute myeloid leukemia. CN-AML blasts isolated from patient bone marrow aspriation were compared to CD34+ cell population from healthy donors by DNA methylation array and affymetrix gene expression microarray. Bisulfited genomic DNA from patients and normal materials were hybirdized to Illumia Infinium Human Methylation 450K Beadchip. Gene expression profiling on selected patient cohort are publish aviable.
2014-07-31 | E-GEOD-58477 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. We performed a comprehensive proteogenomic analysis of bone-marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis included cytogenetic and mutation profiling, and RNA sequencing. This identified five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these subtypes were correlated with patient outcome, but none exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which was only captured in the proteome, was characterized by high expression of mitochondrial proteins and showed poor outcome, with reduced remission rate and shorter overall survival upon treatment with intensive induction chemotherapy. Functional analyses revealed that Mito-AML is metabolically wired towards stronger complex Idependent respiration and is more responsive to treatment with the BCL2-inhibitor venetoclax.
2022-03-08 | PXD028007 | Pride
Project description:Context: In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immune-deficient mice indicating that human acute myeloid leukemia (AML) is organized as a cellular hierarchy driven by self-renewing leukemia stem cells (LSC). This model has significant implications for the development of novel therapies, but its clinical significance remains unclear. Objective: To measure associations between a leukemic stem cell expression signature and clinical outcomes in AML. Design, Setting, and Patients: We defined a gene expression signature of LSC-enriched subpopulations from primary AML patient samples and xenografts, based on a functional definition in transplantation assays. Using previously published gene expression data of bulk AML from four independent cohorts totaling 1047 patients, we performed a retrospective cohort study, defining an LSC score and evaluating it for associations with known predictors of risk including cytogenetic subtype and molecular mutations, and as an independent prognostic factor. Main Outcome Measures: Reproducible associations between a leukemic stem cell signature and overall, event-free, and relapse-free survival. Results: The LSC score was similar across most AML subtypes, but was lower in promyelocytic leukemia, and prognostically favorable cases harboring NPM1 or CEBPA mutations. Strikingly, high scores associated with inferior overall (OS), event-free (EFS), and relapse-free survival (RFS) in these independent cohorts, whether considering patients with a normal karyotype [hazard ratio (HR) range for OS 1.13-1.18, p<0.012 in all cases], or those with cytogenetic anomalies (HR range for OS 1.07-1.15, p<0.01 in all cases). In multivariate analysis, the LSC score was associated with poor outcomes independently of age, FLT3 or NPM1 mutations, and cytogenetic risk group, and added to their prognostic value. Conclusions: High expression of a leukemic stem cell gene expression signature is independently associated with adverse outcomes in AML Cellular fractionation and expression profiling of normal and leukemic subsets: Human samples were obtained at the Stanford University Medical Center according to an approved protocol of the Institutional Review Board after informed consent. Normal human bone marrow mononuclear cells were purchased from AllCells Inc. (Emeryville, CA) and human cord blood was obtained from Stanford University. For AML specimens, peripheral blood and/or bone marrow was obtained, and gene expression microarray data were generated using Affymetrix U133 Plus 2.0 microarrays from the following populations purified by fluorescence-activated cell sorting: AML LSC (Lin-CD34+CD38-CD90-, n=7), AML LPC (Lin-CD34+CD38+, n=7), AML Blasts (Lin-CD34-), normal hematopoietic stem cells (HSC, Lin-CD34+CD38-CD90+CD45RA-; bone marrow and cord blood, n=7), multipotent progenitors (Lin-CD34+CD38-CD90-CD45RA-; bone marrow and cord blood, n=7), common myeloid progenitors (Lin-CD34+CD38+CD123+CD45RA-; bone marrow, n=4), granulocyte-monocyte progenitors (Lin-CD34+CD38+CD123+CD45RA+; bone marrow, n=4), and megakaryocyte-erthythrocyte progenitors (Lin-CD34+CD38+CD123-CD45RA-; bone marrow, n=4). Raw data were deposited at the National Center for Biotechnology Information Gene Expression Omnibus (GEO, accession GSE24006). Detailed methods for purification of cellular subsets and clinical features of the corresponding AML patients have been reported previously. Microarray analysis and definition of LSC signature: Fourteen paired LSC and LPC samples from 7 patients described above were combined with 16 paired samples (8 LSC and 8 LPC) from an independent study to produce one dataset for analysis. Individual genes differentially expressed between paired LSC and LPC were identified using Significance Analysis of Microarrays, employing a paired metric (false discovery rate<10%). The ‘LSC signature’ in a given dataset was defined as the first principal component of these genes (the linear weighted sum of gene expression values that summarizes the maximum possible proportion of their total variance) across samples from that dataset. The LSC signature was evaluated across all purified subpopulations described above. To identify biological themes distinguishing LSC from LPC, all genes on microarrays were ranked by their geometric mean difference in expression between paired LSC/LPC samples, and evaluated using Gene Set Enrichment Analysis. Raw microarray data were obtained as Affymetrix CEL files for four publicly available bulk AML gene expression studies from NCBI GEO (GSE12417, n=163 normal-karyotype AML only, with OS outcomes; GSE10358, n=184, OS and EFS; GSE14468, n=527, OS, EFS and RFS) and the National Cancer Institute caArray database (accession willm-00119, n=170 non-FAB M3, OS only). Matrices of re-analyzed data linked below as supplementary files. Ingenuity Pathways Analysis was used to identify interaction networks of genes.
2010-12-22 | E-GEOD-24006 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. 5 normal AML cells were compared with 8 NK deficient AML cells.
2015-07-24 | E-GEOD-50928 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3Amut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this study, the genomic and transcriptomic features influencing outcomes in DNMT3A-mutated AML were examined in a cohort of 884 patients with AML receiving standard chemotherapy. Stratification by NPM1 and FLT3-ITD status revealed worse survival among patients with NPM1 mutations and wild-type FLT3-ITD (NPM1mut/FLT3-ITDwt) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1mut/FLT3-ITDmut, NPM1wt/FLT3-ITDmut, and NPM1wt/FLT3-ITDwt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of TET2mut in patients with AML and DNMT3Amut/NPM1mut/FLT3-ITDwt led to reclassification from favorable risk to intermediate risk in the ELN-2022. RNA-sequencing analysis revealed a distinct transcriptomic profile in patients with TET2mut, highlighting the enrichment of leukemic stem cell signatures and dendritic cell migration, with MMP14, CD200, and CT45A5 identified as key differentially expressed genes. In conclusion, co-mutation patterns strongly affected AML outcomes in patients with DNMT3Amut. Patients with TET2mut constituted a unique subgroup within the ELN-2022 favorable DNMT3Amut/NPM1mut/FLT3-ITDwt group, characterized by distinct transcriptomic features and an unfavorable prognosis.
2025-05-19 | GSE297413 | GEO
Project description:Purpose: Genomic aberrations are of dominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML), and conventional karyotyping-based risk classifications are routinely used in clinical decision making in AML. One of the known limitations of karyotyping is the low sensitivity of this method to detect genomic abnormalities in the sub-megabase (Mb) to ~5 Mb range, and it is currently unclear whether overcoming this limitation with array-based high-resolution karyotyping could be clinically relevant. Furthermore, given the heterogeneity of molecular mechanisms/aberrations that underlie the risks inherent in conventional karyotyping-based risk classifications, it is likely that further refinements in genomic risk prognostication can be achieved. Here, we have analyzed FACS-sorted AML blast-derived and paired buccal DNA from 114 previously untreated prospectively enrolled AML patients for acquired genomic copy number changes and LOH using Affymetrix SNP 6.0 arrays, and we have correlated genomic lesion load and specific chromosomal abnormalities with patient survival. Conclusions: Using multivariate analyses, we found that having ≥2 genomic lesions detected through SNP 6.0 array profiling approximately doubles the risk of death when controlling for age and karyotype-based risk. Finally, we identified an independent negative prognostic impact of p53 mutations, 17p-LOH or both on survival in AML.
2010-11-30 | GSE23452 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. Gene expression analysis were performed on CD56bright and CD56dim NK cells sorted from patients with impaired or normal CD56bright NK cells (n=2 for each patients? group) and from 3 HC
2015-07-24 | E-GEOD-34885 | biostudies-arrayexpress
Project description:Developmental mechanisms play an important role in determining the costs, limits, and evolutionary consequences of phenotypic plasticity. One issue central to these claims is the metaphor of developmental “decoupling,” where alternate morphs result from evolutionarily independent developmental pathways. We test this assumption through a microarray study that explores differences in gene expression between alternate morphs relative to differences between sexes, a classic example of developmental decoupling. We then examine whether morph-biased genes are less conserved, relative to morph-shared genes, as predicted if developmental decoupling relaxes pleiotropic constraints on divergence. We focus on the developing horns and brains of two species of horned beetles with spectacular sexual- and morph-dimorphism in the expression of horns and fighting behavior. We find that patterns of gene expression were as divergent between morphs as they were between sexes. However, overall patterns of gene expression were also highly correlated across morphs and sexes. Morph-biased genes were more evolutionarily divergent, suggesting a role of relaxed pleiotropic constraints or relaxed selection. Together these results suggest that alternate morphs are somewhat developmentally decoupled, and that this decoupling has significant evolutionary consequences. However, alternative morphs may not be as developmentally decoupled as sometimes assumed and such hypotheses of development should be revisited and refined. We compared gene expression in three focal epidermal tissues (head, prothorax, legs) relative to a "control" tissue (dorsal abdominal epidermis) without any outgrowths. We also surveyed gene expression in the brain, relative to ganglionic neural tissue. We compared such patterns of gene expression between two male morphs (horned, fighter and hornless, sneaker males) and between males and females. We focused our array analyses (N = 48 arrays) on Onthophagus taurus (the species for which the array was designed), but also ran 19 arrays on thoracic tissue of Onthophagus nigriventris, a species which expresses thoracic horns as adults (O. taurus expresses head horns). Finally, we included a small subset of arrays (N = 4) directly hybridizing head epidermis tissue of O. taurus male morphs to validate our overall estimates of morph-biased expression. For more detail, refer to Snell-Rood et al. 2010, Evolution.
2010-09-15 | E-GEOD-23425 | biostudies-arrayexpress