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In blood cancers, both are often interconnected as lesions frequently affect transcription factor (TF)\u2010encoding genes. TFs largely function through enhancers, and enhancer deregulation is linked to cancer initiation and progression. Consequently, enhancer\u2010targeting drugs are in trials for several advanced hematologic cancers. However, for cancers not driven by TF\u2010related lesions, it is less clear how their transcriptional programs are established; if oncogenesis involves enhancer\u2010deregulation, and if they are sensitive to therapeutic enhancer\u2010targeting. Here, we explore this for Philadelphia chromosome\u2010positive (Ph+) B\u2010lineage leukemia (B\u2010ALL), the most common B\u2010ALL in adults with a historically poor prognosis. Ph+B\u2010ALL is driven by BCR::ABL1, a kinase without TF\u2010related 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\u2010ALL from other leukemias. Mechanistically, we show that BCR::ABL1 itself induces enhancer activation, through its kinase activity and via kinase\u2010dependent activation of STAT5, ETV5, and MYC. Consequently, BCR::ABL1\u2010induced genes are hypersensitive to enhancer inhibition, and Ph+B\u2010ALL cells are hypersensitive to enhancer\u2010targeting drugs. Enhancer\u2010targeting further improves the efficacy of BCR::ABL1 kinase inhibitors used for Ph+B\u2010ALL therapy, especially in cells from\n                    <jats:italic>IKZF1<\/jats:italic>\n                    <jats:sup>PLUS<\/jats:sup>\n                    patients that most frequently relapse from current treatment, suggesting enhancer\u2010targeting as a potential promising addition to current therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517231","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T22:40:17Z","timestamp":1773009617000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BCR::ABL1\u2010Induced Enhancer Reprogramming Uncovers Hypersensitivity of Ph+B\u2010ALL Cells to Enhancer\u2010Targeting Drugs"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7316-2842","authenticated-orcid":false,"given":"Han 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