Transcription control by the ENL YEATS domain in acute leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA324084 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3616980.fastq.gz | Fastqsanger.gz | |||
| SRR3616990.fastq.gz | Fastqsanger.gz | |||
| SRR3617110.fastq.gz | Fastqsanger.gz | |||
| SRR3616981.fastq.gz | Fastqsanger.gz | |||
| SRR3616991.fastq.gz | Fastqsanger.gz |
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Project description:Recurrent chromosomal translocations involving the mixed lineage leukemia gene (MLL) give rise to highly aggressive acute leukemia associated with poor clinical outcomes. The preferential involvement of chromatin-associated factors in MLL rearrangements belies a dependency on transcriptional control. To identify new targets for therapeutic development in MLL, we performed a genome-scale CRISPR-Cas9 knockout screen in MLL-AF4 leukemia. Among validated targets, we identified the transcriptional regulator, ENL, as an unrecognized dependency particularly indispensable for proliferation. To explain the mechanistic role for ENL in leukemia pathogenesis and the dynamic role in transcription control, we pursued a chemical genetic strategy utilizing targeted protein degradation. ENL loss suppresses transcription initiation and elongation genome-wide, with pronounced effects at genes featuring disproportionate ENL load. Importantly, ENL-dependent leukemic growth was contingent upon an intact YEATS epigenomic reader domain. These findings reveal a novel dependency in acute leukemia and a first mechanistic rationale for disrupting YEATS domains in disease.
2017-02-23 | GSE82117 | GEO
Project description:Recurrent chromosomal translocations involving the mixed lineage leukemia gene (MLL) give rise to highly aggressive acute leukemia associated with poor clinical outcomes. The preferential involvement of chromatin-associated factors in MLL rearrangements belies a dependency on transcriptional control. To identify new targets for therapeutic development in MLL, we performed a genome-scale CRISPR-Cas9 knockout screen in MLL-AF4 leukemia. Among validated targets, we identified the transcriptional regulator, ENL, as an unrecognized dependency particularly indispensable for proliferation. To explain the mechanistic role for ENL in leukemia pathogenesis and the dynamic role in transcription control, we pursued a chemical genetic strategy utilizing targeted protein degradation. ENL loss suppresses transcription initiation and elongation genome-wide, with pronounced effects at genes featuring disproportionate ENL load. Importantly, ENL-dependent leukemic growth was contingent upon an intact YEATS epigenomic reader domain. These findings reveal a novel dependency in acute leukemia and a first mechanistic rationale for disrupting YEATS domains in disease.
2017-02-23 | GSE82116 | GEO
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
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 | GSE162591 | GEO
Project description:Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia
| PRJNA682342 | ENA
Project description:ENL, a stoichiometric component of the Super Elongation Complex (SEC) as well as the histone H3K79 methyltransferase DOT1L complex, is involved in the regulation of transcription elongation. Loss-of-function studies of ENL highlighted an essential role for its chromatin reader YEATS domain in the progression of acute leukemia, suggesting ENL as an attractive therapeutic target for leukemia therapy. Proteolysis targeting chimeras (PROTACs), a class of new therapeutic modalities, have the potential to degrade target proteinsthrough the ubiquitin-proteasome system. PROTACs have the potential to deliver robust therapeutic effects at low doses and infrequent dosing regimens with less side-effects. Here, we designed and synthesized a serial of ENL PROTACs. Through screening by ENL degradation in human leukemia cells, we identified MS47 as a potent ENL PROTAC. MS47 efficiently and specifically degrades ENL in a concentration-dependent and time dependent manner. In line with the mechanism of action of PROTACs, proteasome inhibitors can block ENL degradation mediated by MS47. MS47 suppresses survival and growth of a panel of acute leukemia cells, and efficiently suppresses the expression of ENL target genes, including Hoxa9, Meis1, Myb and Myc. In disseminated xenograft model, MS47 significantly benefits mouse survival, inhibits leukemia cell growth in vivo. No obvious toxic effect shown in toxicity test in vivo. Modest changes occurred on normal hematopoiesis. Together, our study developed a potent ENL PROTAC for leukemia treatment.
2024-09-13 | GSE245925 | GEO
Project description:ENL, a stoichiometric component of the Super Elongation Complex (SEC) as well as the histone H3K79 methyltransferase DOT1L complex, is involved in the regulation of transcription elongation. Loss-of-function studies of ENL highlighted an essential role for its chromatin reader YEATS domain in the progression of acute leukemia, suggesting ENL as an attractive therapeutic target for leukemia therapy. Proteolysis targeting chimeras (PROTACs), a class of new therapeutic modalities, have the potential to degrade target proteinsthrough the ubiquitin-proteasome system. PROTACs have the potential to deliver robust therapeutic effects at low doses and infrequent dosing regimens with less side-effects. Here, we designed and synthesized a serial of ENL PROTACs. Through screening by ENL degradation in human leukemia cells, we identified MS47 as a potent ENL PROTAC. MS47 efficiently and specifically degrades ENL in a concentration-dependent and time dependent manner. In line with the mechanism of action of PROTACs, proteasome inhibitors can block ENL degradation mediated by MS47. MS47 suppresses survival and growth of a panel of acute leukemia cells, and efficiently suppresses the expression of ENL target genes, including Hoxa9, Meis1, Myb and Myc. In disseminated xenograft model, MS47 significantly benefits mouse survival, inhibits leukemia cell growth in vivo. No obvious toxic effect shown in toxicity test in vivo. Modest changes occurred on normal hematopoiesis. Together, our study developed a potent ENL PROTAC for leukemia treatment.
2024-09-13 | GSE245926 | GEO
Project description:To investigate the contribution of ENL YEATS domain and downstream sequences in MLL-ENL leukemogenesis program, we generated MLL-ENL and MLL-ENL ∆YEATS (ENL aa372-559) cell lines by retrovirally introducing these constructs into lineage negative hematopoietic stem and progenitor cells (HSPCs).
2023-02-27 | GSE211523 | GEO
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 | GSE185093 | GEO
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