Somatic mutation in tMDS
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB18718 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1772990_1.fastq.gz | Fastqsanger.gz | |||
| ERR1772990_2.fastq.gz | Fastqsanger.gz | |||
| ERR1772986_1.fastq.gz | Fastqsanger.gz | |||
| ERR1772986_2.fastq.gz | Fastqsanger.gz | |||
| ERR1772987_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 10 |
Similar Datasets
Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To further characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes (FLT3, DNMT3A, IDH1, IDH2, NRAS) in 129 paired NPM1mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1mut loss (n=11). To gain further insight into these NPM1mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1mut loss patients (pts) feature distinct mutational patterns that shared almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways including loss of characteristic NPM1mut associated gene expression patterns. In contrast, profiles of pts with persistent NPM1mut at relapse are reflected by a high overlap of mutations between diagnosis and relapse. Thus, our findings confirm that relapse often originates from persistent leukemic clones, though NPM1mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of “relapse" in a subgroup of cases.
2019-05-14 | GSE128602 | GEO
Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analysis of in vitro-grown hematopoietic cells transduced with AML1-ETO or MLL-AF9
2015-04-22 | E-GEOD-59584 | biostudies-arrayexpress
Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. 5hmC-DIP-seq analysis for distribution of 5hmC in in vitro-grown hematopoietic cells transduced with AML1-ETO
2015-04-22 | E-GEOD-59579 | biostudies-arrayexpress
Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. ChIP-seq analysis for distribution of H3K4me1, H3K27ac, and H3K4me3 histone marks in in vitro-grown hematopoietic cells transduced with AML1-ETO
2015-04-22 | E-GEOD-59580 | biostudies-arrayexpress
Project description:Germline RUNX1 mutations are found in familial platelet disorders with predisposition to acute myelogenous leukemia (FPD/AML). This very rare disease is characterized by thrombocytopenia, platelet dysfunction and a 35% lifetime risk of developing MDS/AML and in rare cases also T-ALL. Here, we focus on a case of a man with a familial history of RUNX1 R174Q mutation who developed at the age of 42 years an EGIL T2-ALL and two years after remission an AML-M0. To investigate whether initial and relapsed leukemic blasts originated from the same clone, we performed CGH array and WES on both blasts populations. In both T2-ALL and AML-M0 samples, CGH array revealed loss of 1p36.32-23 and 17q11.2 and nine other small deletions. Both AML-M0 and T2-ALL demonstrated clonal rearrangements of both TCR (V9-J1-1) and TCR (D2-J1 and D2-J3). 18 genes were found by WES to be mutated in the original clone at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone. MiSeq technology performed on peripheral blood-derived CD34+ cells five years prior T2-ALL development revealed only missense TET2 P1962T mutation at a frequency of 1% suggesting that this mutation in association with germline RUNX1 R174Q mutation led to amplification of a hematopoietic clone susceptible to acquire other transforming alterations. Identification of clonal hematopoiesis with acquired mutations at low frequency in hematopoietic progenitors before leukemia development could clearly serve as a marker of pre-leukemic state and might be helpful in patient care.
2017-07-05 | E-MTAB-4679 | biostudies-arrayexpress
Project description:Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To further characterize the genetic composition of NPM1 mutated (NPM1mut) AML, we assess mutation status of five recurrently mutated oncogenes (FLT3, DNMT3A, IDH1, IDH2, NRAS) in 129 paired NPM1mut samples obtained at diagnosis and relapse. We find a substantial shift in the genetic pattern from diagnosis to relapse including NPM1mut loss (n=11). To gain further insight into these NPM1mut loss cases, we perform whole exome sequencing (WES) and RNA-Seq. At the time of relapse, NPM1mut loss patients (pts) feature distinct mutational patterns that shared almost no somatic mutation with the corresponding diagnosis sample and impact different signaling pathways including loss of characteristic NPM1mut associated gene expression patterns. In contrast, profiles of pts with persistent NPM1mut at relapse are reflected by a high overlap of mutations between diagnosis and relapse. Thus, our findings confirm that relapse often originates from persistent leukemic clones, though NPM1mut loss cases suggest a second “de novo” or treatment-associated AML (tAML) as alternative cause of “relapse" in a subgroup of cases.
2019-05-14 | GSE128603 | GEO
Project description:The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co-occurring mutations including GATA2 lesions, however insights into mechanisms governing this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Conversely, CEBPADM AML gains a competitive advantage through TET2 loss, by decreasing Gata2 promoter demethylation thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.
2023-08-28 | GSE213860 | GEO
Project description:The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co-occurring mutations including GATA2 lesions, however insights into mechanisms governing this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Conversely, CEBPADM AML gains a competitive advantage through TET2 loss, by decreasing Gata2 promoter demethylation thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.
2023-08-28 | GSE213821 | GEO
Project description:The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML); with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co‑occurring mutations; however, insight into the underlying mechanisms for the co-mutational spectra is incomplete. By combining transcriptomic and epigenomic analyses of data from CEBPA-TET2-co-mutant patients with experimental models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by the CEBPANT, mediate recruitment of TET2 to the GATA2 distal hematopoietic enhancer and thereby increase GATA2 expression. Conversely, CEBPADM AML gains a competitive advantage by loss of TET2; decreasing GATA2 promoter demethylation and re-balancing GATA2 levels. Further, demethylating treatment of CEBPA-TET2-co-mutant AML restores GATA2 levels, and prolongs disease latency.
2023-08-28 | GSE214224 | GEO
Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Gene expression profiles from Tet2-/-;AML1-ETO and Tet2fl/fl;AML1-ETO in vitro-grown hematopoietic cells were compared using GeneChip Mouse Gene ST 2.0 Arrays (Affymetrix). Expression changes were investigated at early (passage 2) and late (passage 10) timepoints after Tet2 disruption.
2015-04-22 | E-GEOD-59586 | biostudies-arrayexpress