Unraveling BCR::ABL1-driven enhancer activation and transcriptional reprogramming in Ph B-ALL

B-lineage acute-lymphoblastic leukemia (B-ALL) is driven by genomic lesions and distinct transcriptional programs. Both are often directly linked as most B-ALLs are caused by genetic lesions at transcription factor (TF)-encoding genes. TFs largely mediate their function through gene regulatory ‘enhancer’ elements and enhancer deregulation is known to promote cancer initiation and progression. Consecutively, enhancer-targeting drugs are currently in clinical trials for advanced hematologic cancers such as acute myeloid leukemia and multiple myeloma. However, for B-ALLs not driven by TF-related genetic lesions it is largely unclear how their disease-promoting transcriptional programs are established, if it involves enhancer-deregulation, and if they would be sensitive to therapeutic enhancer-targeting. We explore this here by focusing on Philadelphia chromosome-positive (Ph+) B-ALL, the most common B-ALL in adults with historically poor prognosis. Ph+B-ALL is driven by the BCR::ABL1 kinase, which has no TF-related function. We report that malignant transformation and associated transcriptional reprogramming by BCR::ABL1 is indeed accompanied by substantial enhancer activation and using Hi-C-based methods we connect enhancers to key genes in Ph+B-ALL. Consequently, Ph+B-ALL-specific enhancer signatures differentiate Ph+B-ALL from other leukemias. We further demonstrate that BCR::ABL1-induced enhancer activation depends on its kinase activity and is executed, at least in part, through the BCR::ABL1-activated TF STAT5. Highlighting the importance of enhancers and the potential of their therapeutic targeting, enhancer inhibition through CBP/P300-specific proteolytic degraders (PROTACs) effectively kills Ph+B-ALL cells.