BCR::ABL1-Induced Enhancer Reprogramming Uncovers Hypersensitivity of Ph+B-ALL Cells to Enhancer-Targeting Drugs

Cancer is driven by genomic lesions and malignancy-promoting transcriptional programs. In blood cancers, both are often interconnected as lesions frequently affect transcription factor (TF)-encoding genes. TFs largely function through enhancers, and enhancer deregulation is linked to cancer initiation and progression. Consequently, enhancer-targeting drugs are in trials for several advanced hematologic cancers. However, for cancers not driven by TF-related lesions, it is less clear how their transcriptional programs are established; if oncogenesis involves enhancer-deregulation, and if they are sensitive to therapeutic enhancer-targeting. Here, we explore this for Philadelphia chromosome-positive (Ph+) B-lineage leukemia (B-ALL), the most common B-ALL in adults with a 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. Mechanistically, we show that BCR::ABL1 itself induces enhancer activation, through its kinase activity and via kinase-dependent activation of STAT5, ETV5, and MYC. Consequently, BCR::ABL1-induced genes are hypersensitive to enhancer inhibition, and Ph+B-ALL cells are hypersensitive to enhancer-targeting drugs. Enhancer-targeting further improves the efficacy of BCR::ABL1 kinase inhibitors used for Ph+B-ALL therapy, especially in cells from IKZF1^PLUS patients that most frequently relapse from current treatment, suggesting enhancer-targeting as a potential promising addition to current therapy.