Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures [ATAC-seq]

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 Fast-ATAC-seq was performed on purified leukemia cells from human patients. 10,000 cells were used for library preparation.