2. Academic Validation
  3. BCR::ABL1-Induced Enhancer Reprogramming Uncovers Hypersensitivity of Ph+B-ALL Cells to Enhancer-Targeting Drugs

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

  • Adv Sci (Weinh). 2026 May;13(25):e17231. doi: 10.1002/advs.202517231.
Han Leng Ng 1,  Trudy Lee Glaser 1,  Jintao Zhu 1,  Mark E Robinson 2,  Kadriye N Cosgun 2,  Valeriya Malysheva 3 4 5,  Ozgen Deniz 6,  Nicholas T Crump 1 7,  Kaiyue Helian 1,  Andrew J Innes 1,  Richard Burt 1,  Li Sun 1,  George John 1,  Haibin Zhou 8,  Atsunori Kaneshige 8,  Longchuan Bai 8,  Shaomeng Wang 8,  Mikhail Spivakov 3 4,  Markus Müschen 2,  Niklas Feldhahn 1
Affiliations

Affiliations

  • 1 Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
  • 2 Center of Molecular and Cellular Oncology, Yale University, New Haven, Connecticut, USA.
  • 3 MRC London Institute of Medical Sciences, London, UK.
  • 4 Institute of Clinical Sciences, Faculty of Medicine, Imperial College, London, UK.
  • 5 VIB Center for Molecular Neurology, University of Antwerp, Belgium, VIB Center for AI and Computational Biology, Leuven, Belgium.
  • 6 Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 7 The Hugh and Josseline Langmuir Centre for Myeloma Research, Imperial College London, London, UK.
  • 8 Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan, USA.
PMID: 41764406 DOI: 10.1002/advs.202517231
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 IKZF1PLUS patients that most frequently relapse from current treatment, suggesting enhancer-targeting as a potential promising addition to current therapy.

Keywords

BCR::ABL1; CBP/P300 inhibitors; Ph+B‐ALL; enhancer reprogramming; leukemia.

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