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| Status |
Public on Oct 05, 2022 |
| Title |
Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Acute myeloid leukemia (AML) is characterized by dysregulated transcriptional programs and these programs require support from chromatin regulators to maintain their hyperactive state. Recent studies have identified the histone acylation ‘reader’ ENL as being a critical dependency in AML, but the potential of therapeutic applications targeting this chromatin reader remains poorly understood. Here, we present a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-055, which displaces ENL from chromatin by competitively blocking the interaction of its YEATS domain with acylated histones. We show that TDI-055 treatment preferentially inhibited the proliferation of human leukemia cells harboring MLL translocations or NPM1 mutations. Through a CRISPR/Cas9 saturated mutagenesis screen, we uncovered an ENL mutant that could confer cells resistance to TDI-055, thus providing compelling proof for the on-target activity of the compound. Rapid displacement of ENL from chromatin resulted in decreased recruitment of select ENL-associated complexes and impaired RNA polymerase II elongation which, in turn, led to the suppression of critical leukemogenic gene expression programs. Finally, pharmacological inhibition of ENL in vivo led to reduced AML growth and prolonged survival in cell line and patient-derived xenograft (PDX) models. Collectively, these results provide critical evidence and mechanistic insights to establish inhibition of ENL as a potential therapeutic strategy against molecularly defined AML, laying the foundation for rapid clinical translation of this approach.
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| Overall design |
AFF4, Pol II, Pol II S2P, DOT1L, H3K79me2, PAF1 ChIP-seq for MV411 cells, Flag-ENL ChIP-seq for MOLM13 cells; AFF1, DOT1L, PolIIS2P ChIP-seq data of the MV4;11 cell treated with DMSO and TDI-055 for 0.5 or 2h.
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| Contributor(s) |
Wan L, Liu Y, Li H, Li Q |
| Citation(s) |
36053276 |
| Submission date |
Sep 30, 2021 |
| Last update date |
Jan 04, 2023 |
| Contact name |
liling Wan |
| E-mail(s) |
Liling.Wan@Pennmedicine.upenn.edu
|
| Organization name |
University of Pennsylvania Perelman School of Medicine
|
| Department |
Department of Cancer Biology
|
| Lab |
Wan lab
|
| Street address |
751 BRB II/III 421 Curie Boulevard
|
| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
| |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL30173 |
NextSeq 2000 (Homo sapiens) |
|
| Samples (25)
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| This SubSeries is part of SuperSeries: |
| GSE185094 |
Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia |
|
| Relations |
| BioProject |
PRJNA767642 |
| SRA |
SRP339498 |
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