Gene expression profiles of mono- and biallelic CEBPA mutations in cytogenetically normal AML
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE15210 | GEO | 2009/12/31
SECONDARY ACCESSION(S): PRJNA116449
REPOSITORIES: GEO
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Project description:Purpose: CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal AML (CN-AML). Patients and Methods: 467 homogeneously treated CN-AML patients were subdivided into moCEBPA, biCEBPA and wildtype (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3 and MLL genes. Furthermore, we obtained gene expression profiles (GEP) for a subgroup of 61 patients using oligonucleotide microarrays. 61 bone-marrow samples from CN-AML patients were analyzed using Affymetrix HG-U133 oligonucleotide microarrays (Affymetrix, Santa Clara, CA). Sample preparation, hybridization and image acquisition were performed according to standard Affymetrix protocols. Custom chip definition files based on the GeneAnnot database were used for data analysis (Ferrari et al, BMC Bioinformatics 8:446). The twilight algorithm was used to comapre gene expression profiles of patients with wildtype CEBPA and mono- and biallelic CEBPA mutations.
2010-05-16 | E-GEOD-15210 | biostudies-arrayexpress
Project description:Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBP? transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBP?-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and upregulates the microRNA expression. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients.
2012-10-04 | E-MTAB-1320 | biostudies-arrayexpress
Project description:Although approximately 80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), over half of them relapse. Better identification of patients who are likely to relapse can help inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML younger than 60 years who achieved a CR after induction treatment with standard “7+3” chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact on outcome (i.e., CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature strongly predictive of patient relapse (area under the curve [AUC]=0.81). The signature consisted of seven coding genes: GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55, and three long non-coding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P<.001), after adjustment for the FLT3-ITD, CEBPA and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature’s strong predictive value with AUC=0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients likely to relapse.
2021-03-16 | GSE165430 | GEO
Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) comprise between forty and fifty percent of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group molecular aberrations such as FLT3ITD, NPM1 and CEBPA mutations recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer including AML. We investigated in total 89 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them to normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (p=0.0004 and 0.04, respectively). Genome-wide methylation levels were elevated in IDH mutated samples (p=0.006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (p<0.0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression free (OR 0.47, p=0.01) and overall survival (OR 0.36, p=0.001). In summary, genome wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML. Genome wide methylation pattern study of cytogenetically normal AML
2011-09-20 | E-GEOD-32251 | biostudies-arrayexpress
Project description:Identification of Acquired Copy Number Alterations and Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia Using High-Resolution Single Nucleotide Polymorphism Analysis Recent advances in genome-wide single nucleotide polymorphism (SNP) analyses have revealed previously unrecognized microdeletions and uniparental disomy (UPD) in a broad spectrum of human cancers. As acute myeloid leukemia (AML) represents a genetically heterogeneous disease, this technology might prove helpful especially for cytogenetically normal AML (CN-AML) cases. Thus, we performed high-resolution SNP analyses in 157 adult cases of CN-AML. Regions of acquired UPD were identified in 12% of cases and most frequently affected chromosomes 6p, 11p, and 13q. Notably, acquired UPD was invariably associated with mutations in NPM1 or CEBPA that impair hematopoietic differentiation (P=0.008), suggesting that UPDs may preferentially target genes that are essential for proliferation and survival of hematopoietic progenitors. Acquired copy number alterations (CNAs) were detected in 49% of cases with losses found in two or more cases affecting e.g. chromosome bands 3p13-p14.1 and 12p13. Furthermore, we identified two cases with a cryptic t(6;11) as well as several non-recurrent aberrations pointing to leukemia relevant regions. With regard to clinical outcome, there appeared to be an association between UPD 11p and UPD 13q cases with overall survival. These data demonstrate the potential of high-resolution SNP analysis for identifying genomic regions of potential pathogenic and clinical relevance in AML.
2009-12-01 | GSE19101 | GEO
Project description:Cytogenetically normal acute myeloid leukemia (CN-AML) comprise between forty and fifty percent of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group molecular aberrations such as FLT3ITD, NPM1 and CEBPA mutations recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer including AML. We investigated in total 89 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them to normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (p=0.0004 and 0.04, respectively). Genome-wide methylation levels were elevated in IDH mutated samples (p=0.006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (p<0.0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression free (OR 0.47, p=0.01) and overall survival (OR 0.36, p=0.001). In summary, genome wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML.
2011-09-21 | GSE32251 | GEO
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: DNA methylation profiling Direct comparison of DNA methylation in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression. Two control groups are included: 8 CD34+ bone marrow samples from healthy donors and 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.
2010-05-07 | E-GEOD-14417 | biostudies-arrayexpress
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Experiment Overall Design: Direct comparison of gene expression in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression, and with 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.
2009-01-24 | E-GEOD-14479 | biostudies-arrayexpress
Project description:We have previously shown that expression levels of 48 long non-coding RNAs (lncRNAs) can generate a prognostic lncRNA score that independently associates with outcome of older patients (aged ≥ 60 years) with cytogenetically normal acute myeloid leukemia (CN-AML). However, the techniques that were used to identify and measure prognostic lncRNAs are not tailored for real-life clinical testing. Herein we report on an assay (based on the nCounter platform), which is designed to produce targeted measurements of prognostic lncRNAs in a clinically friendly manner. We analyzed an independent cohort of 76 older CN-AML patients and found that the nCounter assay yielded reproducible measurements and that the lncRNA score retained its prognostic value; patients with favorable lncRNA scores were more likely to achieve a complete remission (CR, P=0.009) and have longer diseased-free (DFS, P=0.05), overall (OS, P=0.02) and event-free survival (EFS, P=0.002) than patients with unfavorable lncRNA scores. In multivariable analyses, lncRNA score status independently associated with CR rates (P=0.02), as well as OS (P=0.02) and EFS (P=0.02) duration. To gain biological insights, we examined a dataset of older CN-AML patients, previously analyzed with RNA sequencing. We found genes involved in immune response and B cell receptor signaling (for which targeted inhibitors are currently available) to be enriched in patients with unfavorable lncRNA scores. We conclude that clinically applicable lncRNA profiling is feasible and potentially useful for risk stratification of older CN-AML patients. In addition we identify potentially targetable molecular pathways that are active in the high-risk patients with unfavorable lncRNA scores.
2019-05-09 | GSE130923 | GEO
Project description:The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.
2019-08-08 | PXD011359 | Pride