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Series GSE185093 Query DataSets for GSE185093
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
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.
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.
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
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
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (25)
GSM5606322 MV411.AFF1.DMSO.24h [ChIP-Seq]
GSM5606323 MV411.AFF1.TDI-055.24h [ChIP-Seq]
GSM5606324 MV411.input.24h [ChIP-Seq]
This SubSeries is part of SuperSeries:
GSE185094 Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia
BioProject PRJNA767642
SRA SRP339498

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE185093_RAW.tar 2.9 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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