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@ARTICLE{Shah:298920,
      author       = {V. Shah$^*$ and G. Giotopoulos and H. Osaki and M.
                      Meyerhöfer$^*$ and E. Meduri and A. Gallego-Crespo$^*$ and
                      M. A. Behrendt$^*$ and M. Saura-Pañella$^*$ and A. Tarkar
                      and B. Schubert$^*$ and H. Yun and S. J. Horton and S.
                      Agrawal-Singh and P. S. Haehnel$^*$ and F. Basheer and D.
                      Lugo and I. Eleftheriadou and O. Barbash and A. Dhar and M.
                      W. M. Kühn$^*$ and B. Guezguez$^*$ and M. Theobald$^*$ and
                      T. Kindler$^*$ and P. Gallipoli and P. Yeh and M. A. Dawson
                      and R. K. Prinjha and B. J. P. Huntly and D. Sasca$^*$},
      title        = {{A}cute resistance to {BET} inhibitors remodels
                      compensatory transcriptional programs via p300
                      coactivation.},
      journal      = {Blood},
      volume       = {145},
      number       = {7},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2025-00356},
      pages        = {748 - 764},
      year         = {2025},
      abstract     = {Initial clinical trials with drugs targeting epigenetic
                      modulators, such as bromodomain and extraterminal protein
                      (BET) inhibitors, demonstrate modest results in acute
                      myeloid leukemia (AML). A major reason for this involves an
                      increased transcriptional plasticity within AML, which
                      allows the cells to escape therapeutic pressure. In this
                      study, we investigated the immediate epigenetic and
                      transcriptional responses after BET inhibition and
                      demonstrated that BET inhibitor-mediated release of
                      bromodomain-containing protein 4 from chromatin is
                      accompanied by acute compensatory feedback that attenuates
                      downregulation or even increases the expression of specific
                      transcriptional modules. This adaptation is marked at key
                      AML maintenance genes and is mediated by p300, suggesting a
                      rational therapeutic opportunity to improve outcomes by
                      combining BET and p300 inhibition. p300 activity is required
                      during all steps of resistance adaptation; however, the
                      specific transcriptional programs that p300 regulates to
                      induce resistance to BET inhibition differ, in part, between
                      AML subtypes. As a consequence, in some AMLs, the
                      requirement for p300 is highest during the earlier stages of
                      resistance to BET inhibition, when p300 regulates
                      transitional transcriptional patterns that allow
                      leukemia-homeostatic adjustments. In other AMLs, p300 shapes
                      a linear resistance to BET inhibition and remains critical
                      throughout all stages of the evolution of resistance.
                      Altogether, our study elucidates the mechanisms that
                      underlie an 'acute' state of resistance to BET inhibition,
                      achieved through p300 activity, and how these mechanisms
                      remodel to mediate 'chronic' resistance. Importantly, our
                      data also suggest that sequential treatment with BET and
                      p300 inhibition may prevent resistance development, thereby
                      improving outcomes.},
      keywords     = {Humans / Leukemia, Myeloid, Acute: drug therapy / Leukemia,
                      Myeloid, Acute: genetics / Leukemia, Myeloid, Acute:
                      metabolism / Leukemia, Myeloid, Acute: pathology / Drug
                      Resistance, Neoplasm: drug effects / Drug Resistance,
                      Neoplasm: genetics / E1A-Associated p300 Protein: metabolism
                      / E1A-Associated p300 Protein: antagonists $\&$ inhibitors /
                      E1A-Associated p300 Protein: genetics / Transcription
                      Factors: genetics / Transcription Factors: antagonists $\&$
                      inhibitors / Transcription Factors: metabolism / Gene
                      Expression Regulation, Leukemic: drug effects /
                      Transcription, Genetic: drug effects / Cell Line, Tumor /
                      Animals / Mice / Nuclear Proteins: genetics / Nuclear
                      Proteins: metabolism / Nuclear Proteins: antagonists $\&$
                      inhibitors / p300-CBP Transcription Factors: metabolism /
                      p300-CBP Transcription Factors: antagonists $\&$ inhibitors
                      / Bromodomain Containing Proteins / Cell Cycle Proteins /
                      E1A-Associated p300 Protein (NLM Chemicals) / EP300 protein,
                      human (NLM Chemicals) / Transcription Factors (NLM
                      Chemicals) / BRD4 protein, human (NLM Chemicals) / Nuclear
                      Proteins (NLM Chemicals) / p300-CBP Transcription Factors
                      (NLM Chemicals) / Bromodomain Containing Proteins (NLM
                      Chemicals) / Cell Cycle Proteins (NLM Chemicals)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39651888},
      doi          = {10.1182/blood.2022019306},
      url          = {https://inrepo02.dkfz.de/record/298920},
}