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

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: Ph+B-ALL leukaemia cell lines (TOM-1 and SUP-B15) were treated in cell culture with DMSO or 100nM Ponatinib for 24h and then harvested for PCHi-C. In addition, primary leukaemia cells from a Ph+B-ALL patient (BAL08) were ex vivo cultured on OP9 feeder cells for 3 weeks and then treated with DMSO or 100nM Ponatinib for 24h and harvested for PCHi-C. For comparison, Ph+ CML cells (K562) were processed as Ph+B-ALL cells and subjected to PCHI-C. In addition, primary B-cell precursors (bone marrow CD19+CD10+) were directly subjected to PCHi-C.