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 | GSE82116 | 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 | GSE82117 | 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:Transcriptional regulatory proteins are frequent drivers of oncogenesis and common targets for drug discovery. The transcriptional co-activator, ENL, which binds to chromatin through an acetyllysine reader YEATS domain, is preferentially required for the survival and pathogenesis of acute leukemia. Small molecules that inhibit the ENL YEATS domain show anti-leukemia effects in preclinical models, which is thought to be caused by the downregulation of pro-leukemic ENL target genes. However, the transcriptional effects of ENL YEATS domain inhibitors have not been studied in models of intrinsic or acquired resistance and, therefore, the connection between proximal transcriptional effects and downstream anti-proliferative effects is poorly understood. To address this, we identified models of intrinsic and acquired resistance and used them to study the effects of ENL YEATS domain inhibitors. We first discovered that ENL YEATS domain inhibition produces similar transcriptional responses in naive models of sensitive and resistant leukemia. We then performed a CRISPR/Cas9-based genetic modifier screen and identified in-frame deletions of the essential transcriptional regulator, PAF1, that confer resistance to ENL YEATS domain inhibitors. Using isogenic models of PAF1-mediated resistance, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL antagonists.
2025-12-02 | GSE304765 | 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:Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia
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Project description:Hotspot gain-of-function mutations in the YEATS domain of the histone reader protein ENL have been identified in Wilms’ tumor. To investigate the pathogenic role of these cancer-associated ENL mutations in kidney development and tumorigenesis in vivo, we generated conditional knock-in mouse models mimicking patient-derived ENL YEATS mutations. Mice with heterozygous expression of ENLT mutants in either Six2+ nephrogenic or Foxd1+ stromal lineage exhibit severe yet distinct defects in kidney development, both resulting in neonatal lethality. The Six2-ENLT mutant kidney rudiments display compromised cap mesenchyme, scant proximal tubules and cystic glomeruli, indicative of premature commitment and differentiation blockade during nephrogenesis. Bulk and spatial transcriptomic analyses uncover aberrant activation of Hox genes and genes involved in cell fate commitment, especially the Wnt signaling pathway, in ENLT mutant-expressing nephrogenic cells. In contrast, the Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, accompanied with dysregulation of stromal genes involved in nephrogenesis and stroma-nephron crosstalk. Collectively, our study sheds lights on how ENL YEATS domain mutations impede nephrogenesis through different pathways in nephrogenic and stromal lineages, paving the way for further investigations into their roles in tumorigenesis.
2025-02-20 | GSE266256 | GEO
Project description:Hotspot gain-of-function mutations in the YEATS domain of the histone reader protein ENL have been identified in Wilms’ tumor. To investigate the pathogenic role of these cancer-associated ENL mutations in kidney development and tumorigenesis in vivo, we generated conditional knock-in mouse models mimicking patient-derived ENL YEATS mutations. Mice with heterozygous expression of ENLT mutants in either Six2+ nephrogenic or Foxd1+ stromal lineage exhibit severe yet distinct defects in kidney development, both resulting in neonatal lethality. The Six2-ENLT mutant kidney rudiments display compromised cap mesenchyme, scant proximal tubules and cystic glomeruli, indicative of premature commitment and differentiation blockade during nephrogenesis. Bulk and spatial transcriptomic analyses uncover aberrant activation of Hox genes and genes involved in cell fate commitment, especially the Wnt signaling pathway, in ENLT mutant-expressing nephrogenic cells. In contrast, the Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, accompanied with dysregulation of stromal genes involved in nephrogenesis and stroma-nephron crosstalk. Collectively, our study sheds lights on how ENL YEATS domain mutations impede nephrogenesis through different pathways in nephrogenic and stromal lineages, paving the way for further investigations into their roles in tumorigenesis.
2025-02-20 | GSE283433 | GEO
Project description:Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [RNA-Seq]
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