TY  - JOUR
AU  - Shah, Viral
AU  - Giotopoulos, George
AU  - Osaki, Hikari
AU  - Meyerhöfer, Markus
AU  - Meduri, Eshwar
AU  - Gallego-Crespo, Aaron
AU  - Behrendt, Malte A
AU  - Saura-Pañella, Maria
AU  - Tarkar, Aarti
AU  - Schubert, Benedict
AU  - Yun, Haiyang
AU  - Horton, Sarah J
AU  - Agrawal-Singh, Shuchi
AU  - Haehnel, Patricia S
AU  - Basheer, Faisal
AU  - Lugo, Dave
AU  - Eleftheriadou, Ioanna
AU  - Barbash, Olena
AU  - Dhar, Arindam
AU  - Kühn, Michael W M
AU  - Guezguez, Borhane
AU  - Theobald, Matthias
AU  - Kindler, Thomas
AU  - Gallipoli, Paolo
AU  - Yeh, Paul
AU  - Dawson, Mark A
AU  - Prinjha, Rab K
AU  - Huntly, Brian J P
AU  - Sasca, Daniel
TI  - Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 coactivation.
JO  - Blood
VL  - 145
IS  - 7
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-00356
SP  - 748 - 764
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Leukemia, Myeloid, Acute: drug therapy
KW  - Leukemia, Myeloid, Acute: genetics
KW  - Leukemia, Myeloid, Acute: metabolism
KW  - Leukemia, Myeloid, Acute: pathology
KW  - Drug Resistance, Neoplasm: drug effects
KW  - Drug Resistance, Neoplasm: genetics
KW  - E1A-Associated p300 Protein: metabolism
KW  - E1A-Associated p300 Protein: antagonists & inhibitors
KW  - E1A-Associated p300 Protein: genetics
KW  - Transcription Factors: genetics
KW  - Transcription Factors: antagonists & inhibitors
KW  - Transcription Factors: metabolism
KW  - Gene Expression Regulation, Leukemic: drug effects
KW  - Transcription, Genetic: drug effects
KW  - Cell Line, Tumor
KW  - Animals
KW  - Mice
KW  - Nuclear Proteins: genetics
KW  - Nuclear Proteins: metabolism
KW  - Nuclear Proteins: antagonists & inhibitors
KW  - p300-CBP Transcription Factors: metabolism
KW  - p300-CBP Transcription Factors: antagonists & inhibitors
KW  - Bromodomain Containing Proteins
KW  - Cell Cycle Proteins
KW  - E1A-Associated p300 Protein (NLM Chemicals)
KW  - EP300 protein, human (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - BRD4 protein, human (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - p300-CBP Transcription Factors (NLM Chemicals)
KW  - Bromodomain Containing Proteins (NLM Chemicals)
KW  - Cell Cycle Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39651888
DO  - DOI:10.1182/blood.2022019306
UR  - https://inrepo02.dkfz.de/record/298920
ER  -