BCR::ABL1-induced enhancer reprogramming uncovers hypersensitivity of Ph+B-ALL cells to enhancer-targeting drugs

To better understand how BCR::ABL1 establishes the Ph+B-ALL-defining transcriptional program, we adopted an integrative multi-omics approach to study the transcriptome, enhancer activities, and 3-dimensional interactions of enhancers with target genes in Ph+B-ALL cells. We performed an in-depth analysis of cells from human Ph+B-ALL patients and a murine Ph+B-ALL model using ChIP-Seq, RNA-Seq, and Hi-C-based methods to link enhancers to the promoters they regulate. Overall design: ATAC-Seq was performed on primary leukaemia cells from a Ph+B-ALL patient and on two Ph+B-ALL cell lines (TOM-1 and SUP-B15) according to the Omni-ATAC-seq protocol (https://doi.org/10.1038/protex.2017.096). Cells were kept in cell culture under standard conditions and treated for 24h with 100nM Ponatinib or DMSO as control. Primary BAL08 cells were cultured on irradiated OP9 feeeder cells for 3 weeks before experiment.