Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures.

B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of molecular subtypes spanning a range of aberrant chromosomal rearrangements and chimeric fusions driving malignancy. While transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with precursor B-cells identified candidate cell-of-origin for B-ALL cell samples as well as B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. Strikingly, we also identified that over 20% of B-ALL accessible chromatin sites exhibiting strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that promote this subtype-specific chromatin architectures. We further mapped over 9000 inherited genetic variants that contribute to variability in chromatin accessibility among patient samples. Overall, this large dataset and associated analyses offer a unique window into the gene regulatory landscape of B-ALL. Our data suggest that differences in chromatin architecture are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks and transcriptional changes between precursor B-cells and B-ALL, as well as among B-ALL subtypes.