Ph+B-ALL is defined by BCR::ABL1-induced enhancer reprogramming and hypersensitivity to enhancer-targeting drugs

Cancer is driven by genomic lesions and malignancy-promoting transcriptional programs. In blood cancers, both are often directly linked as lesions frequently affect transcription factor (TF) or epigenetic co-factor-encoding genes. Transcriptional regulation is largely mediated through ‘enhancers’ and their deregulation repeatedly linked to cancer initiation and progression. Consequently, enhancer-targeting drugs are in trials for several advanced hematologic cancers. However, for cancers not driven by such lesions, it is often unclear how their transcriptional programs are established, if it involves enhancer-deregulation, and if they are sensitive to enhancer-targeting. Here, we explore this for Philadelphia chromosome-positive (Ph+) B-lineage leukemia (B-ALL), the most common B-ALL in adults with historically poor prognosis. Ph+B-ALL is driven by BCR::ABL1, a kinase without TF-related function. We report that malignant transformation and transcriptional reprogramming by BCR::ABL1 is indeed defined by enhancer reprogramming and that enhancer signatures differentiate Ph+B-ALL from other leukemias. BCR::ABL1 itself induces enhancer activation through its kinase activity and by co-opting signaling-induced TFs. In turn, BCR::ABL1-induced genes are hypersensitive to enhancer-targeting drugs, and their application induces cell death of Ph+B-ALL cells including from poor-prognosis/high-risk IKZF1 ^PLUS patients. Finally, low-dose enhancer-targeting improves the efficacy of BCR::ABL1 kinase inhibitors, suggesting enhancer-targeting as a promising potential addition to current therapy. *Han Leng Ng and Trudy Lee Glaser contributed equally.