Mullighan_GL_reALL WGS1 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001005506 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:WXS files for Mullighan_GL_reALL paper titled "Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia"
| EGAD00001005509 | EGA
Project description:RNAseq files for Mullighan_GL_reALL RNASEQ2 paper titled "Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia"
| EGAD00001005510 | EGA
Project description:RNASeq files for Mullighan_GL_reALL RNASEQ1 paper titled "Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia"
| EGAD00001005511 | EGA
Project description:WGS files for Genomic Landscape ALL paper titled "The genomic landscape of pediatric acute lymphoblastic leukemia"
| EGAD00001008600 | EGA
Project description:Additional WGS files for Genomic Landscape ALL paper titled "The genomic landscape of pediatric acute lymphoblastic leukemia"
| EGAD00001010270 | EGA
Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP
Project description:Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. Up to 20% of children will suffer relapse and face a poor prognosis. Our recent work on the evolution of the epigenetic landscape from diagnosis to relapse demonstrates both substantial diversity in the chromatin landscape as well as shared relapse-specific superenhancer activation, highlighting the importance of chromatin changes in disease progression. However, there is a gap in our understanding of B-ALL progression through the lens of three-dimensional (3D) chromosome topology. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance in B-ALL, we performed Hi-C, ATAC-seq, and RNA-seq on 12 matched primary pediatric leukemia specimens at diagnosis and relapse. Mapping of structural variations (SVs) using Hi-C data revealed previously unidentified stable, diagnosis-specific, and relapse-specific SVs providing further evidence for clonal evolution as a mechanism for drug resistance. Moreover, Hi-C analysis revealed genome wide chromatin remodeling specifically in terms of A/B compartments, TAD interactivity, and chromatin loops. Integration with ATAC-seq and RNA-seq datasets revealed strong correlation with both gene expression and chromatin accessibility. Additionally, we identified recurrent A/B compartments and TAD interactivity changes across the patient cohort for which we were able to demonstrate a crucial role in the clonal evolution of B-ALL. Shared changes in 3D genome organization drive the expression of genes/pathways previously implicated in drug resistance as well. Lastly, enrichment analysis revealed key upstream regulators of 3D genome architecture in B-ALL disease progression. These results extend the landscape of genetic alterations in relapsed B-ALL through the addition of the 3D genomic landscape and identify a breadth of novel therapeutic targets.
2024-05-01 | GSE222686 | GEO
Project description:Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. Up to 20% of children will suffer relapse and face a poor prognosis. Our recent work on the evolution of the epigenetic landscape from diagnosis to relapse demonstrates both substantial diversity in the chromatin landscape as well as shared relapse-specific superenhancer activation, highlighting the importance of chromatin changes in disease progression. However, there is a gap in our understanding of B-ALL progression through the lens of three-dimensional (3D) chromosome topology. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance in B-ALL, we performed Hi-C, ATAC-seq, and RNA-seq on 12 matched primary pediatric leukemia specimens at diagnosis and relapse. Mapping of structural variations (SVs) using Hi-C data revealed previously unidentified stable, diagnosis-specific, and relapse-specific SVs providing further evidence for clonal evolution as a mechanism for drug resistance. Moreover, Hi-C analysis revealed genome wide chromatin remodeling specifically in terms of A/B compartments, TAD interactivity, and chromatin loops. Integration with ATAC-seq and RNA-seq datasets revealed strong correlation with both gene expression and chromatin accessibility. Additionally, we identified recurrent A/B compartments and TAD interactivity changes across the patient cohort for which we were able to demonstrate a crucial role in the clonal evolution of B-ALL. Shared changes in 3D genome organization drive the expression of genes/pathways previously implicated in drug resistance as well. Lastly, enrichment analysis revealed key upstream regulators of 3D genome architecture in B-ALL disease progression. These results extend the landscape of genetic alterations in relapsed B-ALL through the addition of the 3D genomic landscape and identify a breadth of novel therapeutic targets.
2024-05-01 | GSE222685 | GEO
Project description:Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. Up to 20% of children will suffer relapse and face a poor prognosis. Our recent work on the evolution of the epigenetic landscape from diagnosis to relapse demonstrates both substantial diversity in the chromatin landscape as well as shared relapse-specific superenhancer activation, highlighting the importance of chromatin changes in disease progression. However, there is a gap in our understanding of B-ALL progression through the lens of three-dimensional (3D) chromosome topology. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance in B-ALL, we performed Hi-C, ATAC-seq, and RNA-seq on 12 matched primary pediatric leukemia specimens at diagnosis and relapse. Mapping of structural variations (SVs) using Hi-C data revealed previously unidentified stable, diagnosis-specific, and relapse-specific SVs providing further evidence for clonal evolution as a mechanism for drug resistance. Moreover, Hi-C analysis revealed genome wide chromatin remodeling specifically in terms of A/B compartments, TAD interactivity, and chromatin loops. Integration with ATAC-seq and RNA-seq datasets revealed strong correlation with both gene expression and chromatin accessibility. Additionally, we identified recurrent A/B compartments and TAD interactivity changes across the patient cohort for which we were able to demonstrate a crucial role in the clonal evolution of B-ALL. Shared changes in 3D genome organization drive the expression of genes/pathways previously implicated in drug resistance as well. Lastly, enrichment analysis revealed key upstream regulators of 3D genome architecture in B-ALL disease progression. These results extend the landscape of genetic alterations in relapsed B-ALL through the addition of the 3D genomic landscape and identify a breadth of novel therapeutic targets.
2024-05-01 | GSE222679 | GEO
Project description:Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. Up to 20% of children will suffer relapse and face a poor prognosis. Our recent work on the evolution of the epigenetic landscape from diagnosis to relapse demonstrates both substantial diversity in the chromatin landscape as well as shared relapse-specific superenhancer activation, highlighting the importance of chromatin changes in disease progression. However, there is a gap in our understanding of B-ALL progression through the lens of three-dimensional (3D) chromosome topology. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance in B-ALL, we performed Hi-C, ATAC-seq, and RNA-seq on 12 matched primary pediatric leukemia specimens at diagnosis and relapse. Mapping of structural variations (SVs) using Hi-C data revealed previously unidentified stable, diagnosis-specific, and relapse-specific SVs providing further evidence for clonal evolution as a mechanism for drug resistance. Moreover, Hi-C analysis revealed genome wide chromatin remodeling specifically in terms of A/B compartments, TAD interactivity, and chromatin loops. Integration with ATAC-seq and RNA-seq datasets revealed strong correlation with both gene expression and chromatin accessibility. Additionally, we identified recurrent A/B compartments and TAD interactivity changes across the patient cohort for which we were able to demonstrate a crucial role in the clonal evolution of B-ALL. Shared changes in 3D genome organization drive the expression of genes/pathways previously implicated in drug resistance as well. Lastly, enrichment analysis revealed key upstream regulators of 3D genome architecture in B-ALL disease progression. These results extend the landscape of genetic alterations in relapsed B-ALL through the addition of the 3D genomic landscape and identify a breadth of novel therapeutic targets.
2024-05-01 | GSE222675 | GEO