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Prognostic DNA Methylation Patterns in Cytogenetically Normal Acute Myeloid Leukemia are predefined by Stem Cell Chromatin Marks [methylation]

ABSTRACT: 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

ORGANISM(S): Homo sapiens

SUBMITTER: Stefan Deneberg

PROVIDER: E-GEOD-32251 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Prognostic DNA Methylation Patterns in Cytogenetically Normal Acute Myeloid Leukemia are predefined by Stem Cell Chromatin Marks [methylation]

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

RNA-seq expression profiling of NPM1mutated normal-AML with methylome status for HIST1 gene, i.e. H3K27me3 high (N=16) and H3K27me3 low (N=11). Transcriptome was done with Affymetrix HG-133+2.0 and Affymetrix Human Gene 2.0 ST microarrays

Project description:The epigenetic machinery is frequently altered in acute myeloid leukemia (AML). Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22). Here, we further investigate the molecular, functional, and prognosis significance of this epigenetic alteration in NPM1-mutated (NPM1mut) CN-AML. H3K27me3 HIST1high group of patients

2020-08-25 | E-MTAB-6997 | biostudies-arrayexpress

Prognostic DNA Methylation Patterns in CN-AML; a genome wide methylation and gene expression study

Project description:This SuperSeries is composed of the following subset Series: GSE31941: Prognostic DNA Methylation Patterns in Cytogenetically Normal Acute Myeloid Leukemia are predefined by Stem Cell Chromatin Marks [gene expression] GSE32251: Prognostic DNA Methylation Patterns in Cytogenetically Normal Acute Myeloid Leukemia are predefined by Stem Cell Chromatin Marks [methylation] Refer to individual Series

2011-09-20 | E-GEOD-32252 | biostudies-arrayexpress

Gene expression profiles of mono- and biallelic CEBPA mutations in cytogenetically normal AML

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.

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Transcription profiling of human samples of bone morrow or peripheral blood mononuclear cells from adult patients with untreated acute myeloid leukemia to develop a prognostic gene signature for normal karyotype AML

Project description:Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes) which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P=0.002), EFS (HR, 1.73; P=0.001), and RFS (HR, 1.76; P=0.025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR, 4.11; P<0.001), EFS (HR, 2.90; P<0.001), and RFS (HR, 3.14, P<0.001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene expression signature that offers additional prognostic information for patients with CN-AML. Experiment Overall Design: Analysis of 163 samples of bone morrow or peripheral blood mononuclear cells from adult patients with untreated acute myeloid leukemia

2008-10-26 | E-GEOD-12417 | biostudies-arrayexpress

Identification of Acquired Copy Number Alterations and Uniparental Disomies in Cytogenetically Normal AML

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

Prognostic gene signature for normal karyotype AML

2008-08-22 | GSE12417 | GEO

Whole-exome sequencing identifies mutations of BCOR in acute myeloid leukemia with normal karyotype

Project description:Among acute myeloid leukemias (AML) with normal karyotype (CN-AML), NPM1 and CEBPA mutations define WHO provisional entities accounting for ~60% of cases, but the remaining ~40% remains poorly characterized. By whole exome-sequencing (WES) of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3, MLL-PTD and IDH1, we newly identified a clonal somatic mutation in BCOR (BCL6 co-repressor), a gene located in chromosome X. Further analyses showed that BCOR mutations occurred in 11/262 (4.2%) CN-AML cases and represented a substantial fraction (14/82, 17.1%) of CN-AML patients showing the same genetic background as the index patient subjected to WES. BCOR somatic mutations were: i) disruptive events similar to germline BCOR mutations causing the oculo-cranio-facial-dental (OCFD) genetic syndrome; ii) associated with markedly decreased BCOR mRNA levels, absence of full-length BCOR and absent or low expression of a truncated BCOR protein; iii) almost mutually exclusive with NPM1 mutations and frequently associated with DNMT3A and RUNX1 mutations, pointing to a cooperation between these events. Finally, BCOR mutations correlated with poor outcome among a cohort of 160 CN-AML patients (28% versus 66% overall survival at 2 yrs, P=0.024). Our results implicate for the first time BCOR in the pathogenesis of CN-AML without NPM1 mutations.

2011-12-16 | GSE30442 | GEO

Whole-exome sequencing identifies mutations of BCOR in acute myeloid leukemia with normal karyotype

2011-12-16 | E-GEOD-30442 | biostudies-arrayexpress

Expression and Prognostic impact of LncRNAs in AML

Project description:Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis and cell-cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged M-bM-^IM-%60 years) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. We analyzed 148 older cytogenetically normal(CN)-AML patients samples using a custom microarray platform and describe the expression of lncRNAs among the AML samples.

2014-11-26 | E-GEOD-63614 | biostudies-arrayexpress

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