Paradigm Test Set Expression Array
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35186 | GEO | 2012/06/21
SECONDARY ACCESSION(S): PRJNA155957
REPOSITORIES: GEO
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Project description:aCGH data was used in Paradigm analysis for exploration of networks affected by copy number and gene expression changes based on mutation spectra of recurrently mutated genes in breast cancer.
2012-06-21 | GSE35189 | GEO
Project description:Expression data was used in Paradigm analysis for exploration of networks affected by copy number and gene expression changes based on mutation spectra of recurrently mutated genes in breast cancer. cohort of 124 total patients arrayed and analyzed.
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Project description:aCGH data was used in Paradigm analysis for exploration of networks affected by copy number and gene expression changes based on mutation spectra of recurrently mutated genes in breast cancer. 124 patients including 3 Pre-Operative Letrozole and 43 Z1031 patients were arrayed and analyzed
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Project description:This SuperSeries is composed of the following subset Series: GSE35186: Paradigm Test Set Expression Array GSE35189: Paradigm Test Set aCGH Array Refer to individual Series
2012-06-20 | E-GEOD-35191 | biostudies-arrayexpress
Project description: Not available
| S-ECPF-GEOD-35186 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-06-21 | GSE35191 | 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.
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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.
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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.
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Project description:Genomic studies using paired enzalutamide-sensitive and resistant cell models were performed. After transcriptional and copy number profiling, we used PARADIGM to compare the genomic alterations between the parental V16D and resistant MR49F cell models to identify critically deregulated networks to demonstrate the utility of integrative genomic analysis for therapy selection. There were 607 genes and pathway entities that had PARADIGM scores that fell outside the normally distributed range in the MR49F cell line. The top 64 genes were selected for RNAi validation. The most biologically relevant genes between the V16D and MR49F cell line models under enzalutamide treatment conditions were identified as significant by siRNA analysis and deemed biologically relelvant by network and enrichment analyses.
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