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ATAC-seq of Multiple Myeloma

ABSTRACT: Purpose: Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome. Experimental Design: CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for one to six months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA-seq and ATAC-seq. Chromatin accessible regions were used to identify regulatory RNA expression in over 700 samples from newly diagnosed patients in the MMRF CoMMpass trial (NCT01454297). Results: Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. Over 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with IGH translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma. Conclusions: These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167967 | GEO | 2021/03/03

REPOSITORIES: GEO

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Project description:Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients and represents about a quarter of all pediatric malignancies. Past work has characterized B-cell lineage ALL (B-ALL) into molecular subtypes spanning a range of aberrant chromosomal rearrangements and chimeric fusions driving malignancy. While transcriptional and DNA methylation profiling of these subtypes has been extensively examined, the accompanying chromatin landscape and corresponding gene regulatory repertoire is not well characterized for many B-ALL subtypes. To better understand the B-ALL epigenome and gene regulatory network we mapped chromatin accessibility for 11 B-ALL molecular subtypes using assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) across 154 primary patient samples. We uncovered extensive chromatin reprogramming between B-ALL and primary B-cells that drive oncogenic signaling pathways and perturb normal B-cell functions. Strikingly, we also identified 42,457 accessible chromatin sites which exhibit strong subtype enrichment. Subtype enriched sites were shown to have a subtype prediction cross-validation accuracy of nearly 90% within a PCA-LDA classification model framework. Transcription factor (TF) footprint profiling and transcriptomic information further identified candidate subtype-specific driver TFs as well as unique gene regulatory networks among B-ALL subtypes. To better understand how genetic variation impacts chromatin accessibility, we identified 9080 variants that act as ATAC-seq chromatin accessibility quantitative trait loci (ATAC-QTLs) and contribute to chromatin accessibility variability among patient samples. Overall, this large dataset and associated analyses offer a unique window into the gene regulatory landscape of B-ALL that highlight the complexity and heterogeneity of chromatin accessibility among B-ALL molecular subtypes. Keywords: Genome binding/occupancy profiling by high throughput sequencing

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ATAC-seq of Multiple Myeloma

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