EXPERIMENT_TITLE: GSM6928885: PASFIF-D Hi-C; Homo sapiens; Hi-C
EXPERIMENT_DESIGN_LIBRARY_DESCRIPTOR_LIBRARY_CONSTRUCTION_PROTOC: Following FACS, leukemic cells were immediately fixed and crosslinked with 2% formaldehyde at room temperature for 10 minutes. Glycine was added to stop the reaction. Crosslinked cells were washed with PBS and then frozen on dry ice. Crosslinked cell pellets were stored at -80 until ready for processing. Hi-C libraries were generated using the Arima-HiC kit (A410110) with Swift Biosciences® Accel-NGS® 2S Plus DNA Library Kit (Cat # 21024) and Indexing kit (Cat #) according to manufacturer's protocol.
STUDY_DESCRIPTOR_STUDY_ABSTRACT: 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. Overall design: Comparative gene expression profiling analysis of RNA-seq data from 12 matched primary pediatric leukemia specimens at diagnosis and relapse.
SAMPLE_TITLE: PASFIF-D Hi-C
SAMPLE_SAMPLE_ATTRIBUTES_SAMPLE_ATTRIBUTE: [{"TAG": "source_name", "VALUE": "primary bone marrow"}, {"TAG": "disease state", "VALUE": "B-ALL"}, {"TAG": "cell type", "VALUE": "primary bone marrow"}, {"TAG": "genotype", "VALUE": "Diagnosis"}, {"TAG": "geo_loc_name", "VALUE": "missing"}, {"TAG": "collection_date", "VALUE": "missing"}]
Pool_Member_@attributes_sample_title: PASFIF-D Hi-C
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