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

ABSTRACT 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.