Transcription control by the ENL YEATS domain in acute leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE82118 | GEO | 2017/02/23
SECONDARY ACCESSION(S): PRJNA324084
REPOSITORIES: GEO
Similar Datasets
Project description:Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.
| S-EPMC5497220 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-04 | GSE162593 | 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: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:Transcription control by the ENL YEATS domain in acute leukemia
| PRJNA324084 | ENA
Project description:Transcriptional coregulators, 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 coactivator, ENL, as a selective requirement for the survival of acute leukemia and highlighted an essential role for its chromatin reader YEATS domain. Motivated by these discoveries, we executed a screen of nearly 300,000 small molecules and identified an amido-imidazopyridine inhibitor of the ENL YEATS domain (IC50 = 7 μM). Improvements to the initial screening hit were enabled by adopting and expanding upon a SuFEx-based approach to high-throughput medicinal chemistry, ultimately demonstrating that it is compatible with cell-based drug discovery. Through these efforts, we discovered SR-0813, a potent and selective ENL/AF9 YEATS domain inhibitor (IC50 = 25 nM). Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the biological response of AML cells to pharmacological ENL disruption for the first time. Most notably, we discovered that ENL YEATS inhibition is sufficient to selectively suppress ENL target genes, including HOXA9/10, MYB, MYC, and a number of other leukemia proto-oncogenes. Cumulatively, our study establishes YEATS domain inhibition as a viable approach to disrupt the pathogenic function of ENL in acute leukemia and provides the first thoroughly characterized chemical probe for the ENL YEATS domain.
| S-EPMC8161486 | biostudies-literature
Project description:ENL is a transcriptional coactivator that recruits elongation machinery to active cis-regulatory elements upon binding of its YEATS domain-a chromatin reader module-to acylated lysine side chains. Discovery chemistry for the ENL YEATS domain is highly motivated by its significance in acute leukemia pathophysiology, but cell-based assays able to support large-scale screening or hit validation efforts do not presently exist. Here, we report on the discovery of a target engagement assay that allows for high-throughput ligand discovery in living cells. This assay is based on the cellular thermal shift assay (CETSA) but does not require exposing cells to elevated temperatures, as small-molecule ligands are able to stabilize the ENL YEATS domain at 37 °C. By eliminating temperature shifts, we developed a simplified target engagement assay that requires just two steps: drug treatment and luminescence detection. To demonstrate its value for higher throughput applications, we miniaturized the assay to a 1536-well format and screened 37 120 small molecules, ultimately identifying an acyl-lysine-competitive ENL/AF9 YEATS domain inhibitor.
| S-EPMC7384521 | biostudies-literature
Project description:Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the mixed-lineage leukemia (MLL)-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, 11 and 24, with IC50 values below 100 nM in inhibiting the ENL-acetyl-H3 interaction. Both compounds, and their precursor compound 7, displayed strong selectivity toward the ENL YEATS domain over all other human YEATS domains. Moreover, 7 exhibited on-target inhibition of ENL in cultured cells and a synergistic effect with the bromodomain and extraterminal domain inhibitor JQ1 in killing leukemia cells. Together, we have developed selective chemical probes for the ENL YEATS domain, providing the basis for further medicinal chemistry-based optimization to advance both basic and translational research of ENL.
| S-EPMC8486320 | biostudies-literature
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