Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [ChIP-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185093 | GEO | 2022/10/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia [RNA-Seq]

Project description: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.

2022-10-05 | GSE185091 | GEO

Single-Cell multi-omics reveals disrupted gene regulatory landscape and cell differentiation by Wilms tumor-associated ENL mutation in the developing kidney (RNA-Seq)

Project description:ENL is an epigenetic acetylation reader and represents the most frequently mutated epigenetic regulator in Wilms tumor. In this study, we established an in vivo mouse model with the ENL hotspot mutation Enl-T1. Here we performed RNA sequencing (RNA-seq) analysis for human embryonuc kidney cell line HEK293 with ENL-WT, T1 or T2 to study the transcriptional changes induced by ENL mutations and whether those alterations can be rescued by treating the cells with the specific ENL inhibitor TDI-11055.

2024-05-27 | GSE243867 | GEO

Single-Cell multi-omics reveals disrupted gene regulatory landscape and cell differentiation by Wilms tumor-associated ENL mutation in the developing kidney (ChIP-Seq)

Project description:ENL is an epigenetic acetylation reader and represents the most frequently mutated epigenetic regulator in Wilms tumor. In this study, we established an in vivo mouse model with the ENL hotspot mutation Enl-T1. Here we performed ChIP sequencing (ChIP-seq) analysis for human embryonuc kidney cell line HEK293 with ENL-WT or T1 to study the genomic binding site alterations induced by ENL mutation and whether those alterations can be rescued by treating the cells with the specific ENL inhibitor TDI-11055.

2024-05-27 | GSE243866 | GEO

ENL Links Histone Acetylation to Oncogenic Gene Expression in AML

Project description:Cancer cells are characterized by aberrant epigenetic landscapes and often exploit the chromatin machinery to activate oncogenic gene expression programs1. The recognition of modified histones by “reader” proteins constitutes a key mechanism underlying these processes; therefore targeting such pathways holds clinical promise, as exemplified by the recent development of BET bromodomain inhibitors2,3. We recently identified the YEATS domain as a novel acetyllysine-binding module4, yet its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralog AF9, is required for disease maintenance in a variety of acute myeloid leukaemias (AML). CRISPR-Cas9 mediated depletion of ENL led to anti-leukemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies in vitro and ChIP-seq analyses in leukaemia cells revealed that ENL binds to acetylated histone H3, and colocalizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemias. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced RNA polymerase II recruitment on ENL target genes, thus leading to suppression of oncogenic gene expression programs. Importantly, disruption of ENL’s functionality further sensitized leukaemia cells to BET inhibitors. Together, our study identifies ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in AML and suggests that displacement of ENL from chromatin is a promising epigenetic therapy alone or in combination with BET inhibitors for AML

2017-04-05 | GSE80774 | GEO

ENL Links Histone Acetylation to Oncogenic Gene Expression in AML

2017-02-23 | GSE80779 | GEO

Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [RNA-Seq]

Project description:Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia – particularly those driven by multiple lineage leukemia (MLL)-fusion oncogenes. The YEATS domain of ENL, which binds to chromatin by interacting with acyl-lysine side chains, is critical for its pathogenic function in acute leukemiaand highlighted an essential role for its chromatin reader YEATS domain. Motivated by these recent discoveries, we executed a screen of nearly 300,000 small molecules to identify chromatin-competitiveand identified an amido-imidazopyridine inhibitors of the ENL YEATS domain (IC50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to Optimizing an amido-imidazopyridine scaffold with highly parallelized, SuFEx-based medicinal chemistry optimization, we discovered SR-0813 (IC50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of In AML cells, SR-0813 evicts ENL from chromatin, by SR-0813 preferentially suppresseselicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.

2020-12-04 | GSE162592 | GEO

Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [ChIP-Seq]

2020-12-04 | GSE162591 | GEO

Impaired Cell Fate by Gain-of-function Mutations in a Chromatin Reader

Project description:We previously identified the YEATS domain-containing protein ENL as a reader of histone acetylation. Recently, hotspot mutations in ENL were frequently found in Wilms’ tumor, the most common type of pediatric kidney cancer. Here, we report that these cancer-associated mutations in the ENL YEATS domain confer gain of functions in transcriptional control and impair kidney differentiation by driving self-reinforced chromatin targeting. Ectopic expression of ENL mutants in kidney cell lines resulted in transcriptional changes of genes enriched in embryonic nephron progenitors and Wilms’ tumor. When tested in a nephrogenesis assay, ENL mutant expression led to undifferentiated structures resembling those observed in human Wilms’ tumor. Genome-wide analyses revealed that while mutant ENL bound to largely similar genomic loci as wild-type ENL, they exhibited increased occupancy at a subset of targets, including developmentally critical genes such as the HOXA cluster. The cancer-associated mutations enabled self-reinforced recruitment of ENL on chromatin by promoting self-association, resulting in the formation of discrete nuclear puncta that are characteristic of phase-separated biomolecular condensates. Enhanced occupancy of ENL mutants led to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Collectively, our studies represent, to our knowledge, the first discovery that cancer-associated mutations in a chromatin reader drive self-reinforced chromatin targeting, which in turns, perturbs developmental programs and derails normal cell fate control during mammalian development towards an oncogenic path.

2020-01-03 | GSE125186 | GEO

The alternative Nucleosome Remodeling Factor complex sustains acute myeloid leukemia by regulating the accessibility of insulator regions

Project description:Efficient treatment of Acute Myeloid Leukemia (AML) patients remains a challenge despite recent advances. Here using a CRISPRi screen targeting chromatin factors, we identified BPTF as an essential regulator of AML cell survival. We demonstrate that BPTF forms an alternative NURF chromatin remodeling complex with SMARCA5 and BAP18, which regulates the accessibility of a large set of insulator regions in leukemic cells. This ensures efficient CTCF binding and boundary formation between topologically associated domains that is essential for maintaining the leukemic transcriptional programs. We also demonstrate that the well-studied PHD2-BROMO chromatin reader modules of BPTF, while contributing to complex recruitment to chromatin, are dispensable for leukemic cell growth. Taken together, our results uncover how the alternative NURF complex contributes to leukemia and provide a rationale for its targeting in AML.

2023-11-12 | PXD044656 | Pride

Condensate-promoting ENL mutation induces tumorigenesis via chromatin remodeling [RNA-seq]

Project description:Gain-of-function mutations in the chromatin ‘reader’ ENL, identified in AML and Wilms tumor, have been shown to induce aberrant formation of transcriptional condensates in cellular systems. However, the precise role of these mutations and their condensate forming property in tumorigenesis remains unclear. By creating a conditional knock-in mouse model for the most prevalent ENL mutation, we establish ENL mutant as a bona fide oncogenic driver of acute myeloid leukemia in vivo. Heterozygous expression of ENL mutant perturbs the normal hematopoietic hierarchy and results in the aberrant expansion of myeloid progenitors with increased self-renewal property. Furthermore, the ENL mutant remodels histone modifications to alter differentiation processes and drive oncogenic gene expression during hematopoietic development. Importantly, targeted point mutagenesis to disrupt the condensate formation property completely abolishes ENL mutant’s oncogenic function in hematopoietic stem and progenitor cells (HSPCs). Lastly, short-term treatment with a small molecule inhibitor that blocks the acetyl-binding activity of ENL mutant reverts its impact on chromatin and significantly delays leukemia development in mice. Our studies reveal the crucial biological function of mutation-induced transcriptional condensates in chromatin regulation and cancer in vivo and provide proof-of-concept for targeting of pathogenic condensates as a promising therapy for certain cancers.

2024-04-14 | GSE239469 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data